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BULLETIN  OF  THE  UNIVERSITY  OF  WISCONSIN 

Serial  No.  980.     Geaeral  Seriet  No.  764 


A  CENTURY  OF  THE  UNITED  STATES 
"^    PHARMACOPOEIA,  1820-1920 


I— THE  GALENICAL  OLEORESINS 

BY 
ANDREW  G.  DUMEZ 


THESIS  SUBMITTED  FOR  THE  DEGREE  OF  DOCTOR  OF<  PHILOSOPHY 

UNIVERSITY  OF  WISCONSIN 

1917 


Repriated  from  vol.  xix  o(  th« 
Transaction*  of  the  Witconiin 
Academy  of  Scieneei,  Am 
and  Letters. 


PHARMACEUTICAL  PUBLICATIONS  OF  THE 
UNIVERSITY  OF  WISCONSIN 


Monographs 

Price 

Nellie  Wakeman,  Plant  pigments 0.35 

A.  G.  Du  Mez,  The  galenical  oleoresins  0. 50 

H.  A.  Langenhan,  The  arsenical  liquors  (In  preparation) 

BULLETIXS 

A.  F.  Sievers,  On  the  addition  of  organic  acids  to  unsaturated  hy- 
drocarbons       0.20 

Nellie  Wakeman,  The  Monardas,  a  phytochemical  study  0.20 

E.  Kremers,  The  classification  of  carbon  compounds  0 .  40 

H.  A.  Langenhan,  The  alkaloldal  content  of  stramonium  leaves. .     0.25 
E.  R.  Miller,  A  chemical  study  of  the  oils  of  several  species  of 
Eupatorium;  and  A  study  of  the  chemical  and  physical  prop- 
erties of  Wisconsin  wormwood  oil 0.2.") 

E.  R.  Miller,  The  chemistry  of  the  oil  of  Achillea  millefolium,  a 

study  in  economic  drug  culture 0.25 

Grri)i:s 

E.  V.  Ljmn,  Laboratory  guide  to  pharmaceutical  technique 0.25 

Nellie    Wakeman,  Guide   to    chemistry   40.   Plant   chemistry   for 

pharmacy  students  0.20 

E.  Kremers,  A  bibliographic  guide  for  students  of  the  history  of 

pharmacy    0.25 

Station  Reports 

Report  of  the  Director  of  the  Pharmaceutical  Experiment  Station  for 

the  fiscal  year  July  1,  1913,  to  June  30,  1914. 
Report  of  the  Director  of  the  Pharmaceutical  Experiment  Station  for 

the  fiscal  years  July  1,  1914,  to  June  30,  1916. 
Report  of  the  Pharmaceutical  Experiment  Station  for  the  fiscal  vears, 

July  1,  1916,  to  June  .30,  1918. 

Stattox  CTi'cn.M's 
1.)     General  announcement. 
2.)      The  volatile   oil   of  Pi/,  nantri^  m  nhi    hnncoUthnn    l^ursli,    hv   E.   R. 

Miller. 
:•-.)     Medicinal  plants  and  designs,  by  Bernice  Oehler. 
4. )     The  volatile  oil  of  Monarda  fistiilosa  L.,  by  E.  R.  Miller. 
5.)     N.  F.  petroxolins  and  parallel  preparations,  bv  H.  A.  Langenhan 

and  G.  J.  Noel. 
6.)     Preliminary  report  of  the  Conference  on  the   Help   Situation   in 

Wisconsin,  by  its  chairman. 
7.)     Water-soluble  volatile  products  from  peppermint,  by  E.  R.  Miller. 
S.)     The  application  of  the  principles  of  breeding  to  drug  planls,  i)nr- 

ticnlarly  DaUira,  by  C.  M.  Woodworth.      (In  press.) 


BULLETIN  OF  THE  UNIVERSITY  OF  WISCONSIN 

SERIAL  NO.  980.    GENERAL  SERIES  NO.  764 


C^ei^ 


A  CENTURY  OF  THE  UNITED  STATES 
PHARMACOPOEIA,   1820-1920 


I_THE  GALENICAL  OLEORESINS 

BY 
ANDREW  G.  DU  MEZ 


THESIS  SUBMITTED  FOR  THE  DEGREE  OF  DOCTOR  OF  PHILOSOPHY 

UNIVERSITY  OF  WISCONSIN 

1917 


Reprinted  from  vol.  xii  of  the 
Transactions  of  the  Wisconsin 
Academy  of  Sciences,  Arti 
and  Letters. 


Ri<^0 


CONTENTS 


CONTENTS 


PART  I— GENERAL 


Page 

Historical   Introduction    7 

Definition     l"? 

Drugs  used 14 

Solvents  used   15 

Methods  of  preparation 20 

Apparatus  employed 27 

Yield     46 

Chemistry    46 

Physical  and  chemical  proper- 
ties      47 

Physical  properties 47 

Color 47 

Odor 48 

Taste     48 


Page 

Consistence    48 

Solubility 4» 

Specific   gravity    ■•  .  .  49 

Refractive  index    50 

Chemical   properties    51 

Loss  in  weight  on  heating.  .  51 

Ash    content 53 

Acid    number    54 

Saponification  vailue    54 

Iodine  value   (.......  55 

Special  tests    55 

Qualitative   tests    56 

Quantitative    tests    5ft 

Adulterations    5S 


PART   II — INDIVIDUAL    OLEORESINS 


Page 

Oleoresin  of  aspidium    59 

Synonyms 59 

History     61 

Drugs  used,  its  collection,  pres- 
ervation,   etc 62 

IT.  S.  P.     text     and     comments 

thereon     67 

Yield ./ 74 

Chemistry  of  the  oleoresin  and 
of    the    drug    from    which 

prepared    79 

Constituents     of    therapeutic 

importance 86 

Physical  properties 86 

Color     86 

Odor 87 

Taste     .  .  .  .1 87 

Consistence    87 

Solubility      87 

Specific   gravity    i 88 

Refractive   index    90 

Chemical   properties    92 

Loss  in  weight  on  heating  .  .  9S 

Ash    content    93 

Acid    number    94 

Saponification  value    95 

Iodine  vailue 97 

Other  properties    98 


Page 

Special  qualitative  tests 9* 

Tests  for  filicin    99 

Austrian    Pharmacopoeia.  .  99 

Netherlands  Pharmacopoeia  99' 

Hungarian    Pharmacopoeia  99^ 

Tests  for  starch    100 

German  Pharmacopoeia.  .  .  100' 
Test  for  oleoresin  of  Dryop- 

teris  spinulosa    101 

Hausmann's     method 101 

Test  for  castor  oil 101 

Test  for  copper    101 

Special   quantitative  tests    ....  101 
Methods   for   the   determina- 
tion  of  filix   acid 102^ 

Method   of  Kremel    102 

Method  of  Bocchi 10^ 

Method  of  Kraft 102 

Method  of  Fromme   (orig- 
inal)      103 

Method    of    Fromme     (im- 
proved)    .  .1 103 

Method   of  Stoeder '.  103 

Comparison         of        above 

methods 104 

Methods  for  the  determin- 
ation of  crude  filicin  .  .  .  104 
Method  of  Rulle 105 


CONTENTS 


Page 
Method    of    Daccomo    and 

Scoccianti     105 

Method  of  Schmidt 105 

Method  of  Fromme 105 

Influence    of    different    alka- 
llies    on    yield    of    crude 

filicin    106 

Crude     filicin     content     of 

laboratory  properations.  107 
Crude     filicin     content     of 

commercial  samples    .  .  .  108 

Physiological   tests    109 

Method  of  Yagi 109 

Adulterations    .  .  . 110 

Oleoresin  of  capsicum    Ill 

Synonyms    Ill 

History     , 111 

Drugs     used,     its     collection, 

preservation,  etc .  Ill 

U.   S.   P.   text  and  comments 

thereon     112 

Yield     .  ., 117 

Chemistry    of    the    oleoresin 
and    of    the    drug    from 

which  prepared    121 

Constituents    of     therapeutic 

importance    124 

Physical  properties 124 

CoHor     , 124 

Odor      124 

Taste     > 124 

Consistence    124 

Solubility      125 

Specific  gravity 125 

Refractive  index .  126 

Chemical   properties 127 

Loss  in  weight  on  heating  127 

Ash   content    127 

Acid    number  i 128 

Saponification  value 129 

Iodine  value    130 

Special   quantitative   tests.  .  .  131 

Physiological  test    131 

Adulterations    ,.  .  .  132 

Oleoresin  of  cubeb    132 

Synonyms     132 

History     132 

Drug     used,     its     collection, 

preservation,    etc 134 

U.   S.   P.  text  and  comments 

thereon     134 

Yield     139 

Chemistry    of    the    oleoresin 
•  and    of    the    drug    from 

which  prepared    143 

Constituents    of    therapeutic 

k             importance    147 


Page 

Physical  properties 147 

Coilor     147 

Odor   147 

Taste     148 

Consistence    148 

Solubility 148 

Specific   gravity    148 

Refractive  ihdex    149 

Chemical  properties    150 

Loss  in  weight  on  heating  150 

Ash   content 151 

Acid   number    151 

Saponification  value 152 

Iodine  value    153 

Other  properties    154 

Special  qualitative  tests   ....  154 

Method  of  Dietrich 155 

Method  of  Gluecksmann.  .  156 

Austrian    Pharmacopoeia.  .  156 

French  Pharmacopoeia  ...  156 

Swiss  Pharmacopoeia    ....  156 

Hungarian    Pharmacopoeia  156 

German  Pharmacopoeia    .  .  157 

Special  quantitative  tests  ...  157 
Kremel's    method    for   the 
determination    of    cube- 

bic  acid    157 

Adulterations    157 

Oleoresin  of  ginger 158 

Synonyms 158 

History     158 

Drug     used,      its     collection, 

preservation,  etc 158 

U.   S.   P.   text  and  comments 

thereon     160 

Yield     163 

Chemistry    of    the    oileoresin 
and    of    the    drug    from 

which  prepared    167 

Constituents     of    therapeutic 

importance    170 

Physical  properties 171 

Color     171 

Odor 171 

Taste     171 

Consistence    I7i 

Solubility      171 

Specific   gravity    172 

Refractive  index    172 

Chemical   properties 173 

Loss  in  weight  on  heating  173 

Ash  content    174 

Acid   number 175 

Saponification  value    175 

Iodine  value    176 

Special  qualitative  tests   ....  177 
Tests  for  oleoresin  of  cap- 
sicum     , 177 


CONTENTS 


Page 
Method     of     Garnet     and 

Grier     178 

Method  of  La  Wall 178 

Method    of  Nelson    .  . 178 

Special  quantitative   tests    .  .  179 
Methods  for  the  estimation 

of   the    g-ing-erol    content  179 

Method  of  Garnet  and  Grier  179 

Physioilogical   tests    180 

Adulterations    181 

Oleoresin  of  lupulin 181 

Synonyms 181 

History     181 

Drug      used,      its      collection 

preservation,  etc. 182 

U.   S.  P.  text  and  comments 

thereon     183 

Yield     186 

Chemistry    of    the    oleoresin 
and    of    the    drug    from 

which  prepared    .......  187 

Constituents     of    therapeutic 

importance    190 

Physical  properties 191 

Color 191 

Odor 191 

Taste 191 

Consistence    191 

Solubility 191 

Specific   gravity 192 

Refractive   index 192 

Chemical  properties    193 

Loss  in  vsreight  on  heating  193 

Ash   content    194 

Acid   number 195 

Saponification  value    195 

Iodine  value   196 

Adulterations    197 

Oleoresin  of  parsley  fruit   .  .  .  .  197 

Synonyms    197 

History 198 

Drug     used,      its     coQlection, 

preservation,    etc.    198 

U.   S.   P.  text  and  comments 

thereon     199 

Yield     201 

Chemistry    of    the    oleoresin 

and    of    the    drug    from 

which  prepared    . 202 

Constituents    of    therapeutic 

importance 204 


Page 

Physical  properties "SOS 

Color     205 

Odor      205 

Taste     205 

Consistence    205 

Solubility      205 

Specific   gravity    205 

Refractive  index    206 

Chemical  properties    207 

Loss  in  weight  on  heating  207 

Ash    content 207 

Acid   number    208 

Saponification  value    208 

Iodine  value   209 

Adulterations    210 

Oleoresin  of  pepper    !210 

Synonyms    210 

History 210 

Drug     used,      its     collection, 

preservation,  etc 211 

U.   S.   P.   text  and  comments 

thereon     212 

Yield     216 

Chemistry    of    the    oleoresin 
and    of    the    drug    from 

which  prepared    218 

Constituents     of    therapeutic 

importance    222 

PhysicaJl  properties 222 

Color     2122 

Odor      222 

Taste     222 

Consistence    222 

Solubility      222 

Specific   gravity    2122 

Refractive   index    223 

Chemical   properties    224 

Loss  in  weight  on  heating  224 

Ash    content    225 

Acid   number    226 

Saponification  value    226 

Iodine  value 227 

Special  quanitative  tests    ...  228 
Method  for  the  estimation 

of   the   piperine    content  228 

Advilterations    229 

I 

BIBLIOGRAPHY    29 

INDEX    TO    BIBLIOGRAPHY  284 


Abbreviations  Used  for  the  Titles  of  PHARMACOPOEiAe  and 
Treatises  on  Pharmacy. 

AUg.  P. — Strump,  Allgemeine  PJiarmakopoe. 

Argent.  P.  —  Argentine  Pharmacopoeia  —  Farmacopcea  Na- 
cianal  Argentina. 

Aust.  P.  —  Austrian  Pharmacopceia  —  PJiarmacopoea  Austriaca. 

Bad.  P.  —  Baden  Pharmacopoeia  —  Pharmacopoea  Badensis. 

Belg.  P.  —  Belgian  Pharmacopoeia  —  Pliarmacopcea  Belgica. 

Bern.  P.  —  Bernese  Pharmacopoeia  —  Pharmacopoea  Bernensis. 

B.  P.  —  BritisJi  Phdrmacoposa. 

B.  P.  C.  —  BritisJi  Pharmaceutical  Codex. 

Comp.  to  the  U.  S.  P.  —  Companion  to  the  United  States  Phar- 
macopoeia. 

Dan.  P.  —  Danish  Pharmacopoeia  —  Pharmacopoea  Danica. 

Dan.  Mil.  P.  —  Danish  Military  Pharmacopoeia. 

Diet,  of  Pharm.  Sc.  —  Schweringer,  Dictionary  of  Pharmaceu- 
tical Science. 

Fin.  P.  —  Finnish  Pharmacopoeia  —  Pharmacopoea  Fennica. 

Fr.  P.  —  French  Pharmacopoeia  —  Pharmacopoee  Francaise. 

G.  P. — German  Pharmacopoeia — Pharmacopoea  Germanica. 

Geiger's  P.  —  Geiger's  Pharmacopoe. 

Han.  P.  —  Hannoverian  Pharmacopoeia  —  Pharmahopbe  fiir  das 
Koenigreich  Hannover. 

Hess.  P.  —  Hessian  Pharmacopoeia  —  Pharmakopde  fiir  das 
Kurfuerstenthum  Hessen. 

Hung.  P.  —  Hungarian  Pharmacopoeia  —  Pharmacopoea  Hun- 
garica. 

Xtal.  P.  —  Italian  Pharmacopoeia  —  Farmacopoea  TJfficiale  del 
Regno  d' It  alia. 

Jap.  P.  —  Japanese  Pharmacouoeia  —  The  Pharmacopoeia  of 
Japan. 

King's  Am.  Disp.  —  King's  American  Dispensatory, 

Mex.  P.  —  Mexican  Pharmacopoeia  —  Pharmacopoea  Mexicana. 

Nat.  Stand.  Disp.  —  National  Standard  Dispensatory. 

Neth.  P. — Netherlands  Pharmacopoeia  —  Pharmacopoea  Neder- 
landica — Nederlandische  Apotheek. 

Nor.  P.  —  Norwegian  Pharmacopoeia  —  Pharmacopoea  Nor- 
vegica. 


6  ABBREVIATIONS 

Port.   P.  —  Portuguese   Pharmacopoeia  —  Pharmacopcra   Portu- 

gueza. 
Pruss.    P.  —  Prussian    Pharmacopoeia  —  PJiarmacopoea    Bonis- 

sica. 
Roum,    P.  —  Roumanian    Pharmacopoeia  —  PJiarmacopoea    Ro- 

mana. 
Russ.  P. —  Russian  Pharmacopoeia  —  PJiarmacopoea  Russica. 
Schlesw.  Holt.  P.  —  Schleswig-Holstein  Pharmacopoeia — PJiar- 

maJcopoe  fur  ScJileswig  und  Holstein, 
Sp.    P.  —  Spanish    Pharmacopoeia  —  Farmacopoea    Oficial    Es- 

panola. 
Swed.  P.  —  Swedish  Pharmacopoeia  —  PJiarmacopoea  Suecica. 
Swiss  P.  —  Swiss  Pharmacopoeia — PJiarmacopoea  Helvetica. 
U.  S.  Disp.  —  United  States  Dispensatory, 
U.  S.  P.  —  United  States  PJmrmacopceia. 
Univ.  P.  —  Hirsch,  Universal-PJiarmacopoe. 
Ver.  P.  der  Lond.,  Edinb.  und  Dub  .  Med.    Coll.  —  Yereinigte 

PJiarmacopceen  der  Londoner,  EdinhurgJier,  und  Duhliner 

Medicines  Collegien. 


PART  I  —  GENERAL 


Historical  Introduction 

The  type  of  galenical  preparation  now  known  as  an  oleoresin 
has  been  official  in  the  United  States  Pharmacopoeia  since  1850, 
the  oleoresins  of  cubeb  and  pepper  being  the  first  members  of 
this  class  of  preparations  to  receive  recognition,  however,  under 
the  title  of  fluid  extract. 

The  suggestion  for  the  name  oleoresin  appears  to  have  come 
from  Buchner  though  first  applied  as  the  name  of  a  galenical 
by  Peschier.  The  latter,  in  1825,  had  prepared  an  ethereal 
extract  of  male  fern  which  he  designated  Huile  de  Fougere  Male. 
To  this  name,  Buchner  objected,  suggesting  the  title  Extractum 
resinosum.  In  reporting  Peschier 's  work,  however,  Buchner 
•speaks  of  the  constituents  of  the  ethereal  extract  as  the  oelharzige 
BestandtJieile  of  male  fern,  and  later  in  his  account,  he  refers  to 
the  finished  preparation  as  the  oelJiarziges  Extract,  i,  e.  an 
oleoresinous  extract.  It  would  appear,  therefore,  that  when 
Peschier,  in  his  second  account  (1828),  speaks  of  an  oleoresine, 
our  English  oleoresin,  he  evidently  took  his  suggestion  from 
Buchner 's  use  of  the  German  attribute,  oelJiarzig. 

The  suggestion  of  Buchner,  that  the  above  mentioned  pre- 
paration of  male  fern  be  called  an  extract,  appears  to  have  met 
with  general  favor  throughout  Europe  as  is  indicated  by  its  title 
in  the  various  European  pharmacopoeias,  past  and  present. 
Likewise,  such  other  members  of  this  class  of  preparations  as 
have  received  recognition  in  the  European  countries  are  to  be 
found  in  the  respective  pharmacopoeias  of  these  countries  under 
the  heading,  extracta.  In  the  United  States,  a  latinized  form 
of  Peschier 's  title,  oleoresine,  has  been  adopted  and  these  pre- 
parations are  officially  known  as  oleorsinae. 

The  following  table  of  titles  will  give  a  fair  idea  of  the  early 
development  of  the  synonymy  of  these  preparations : 


DU  MEZ— THE  GALENICAL  OLEORESINS. 


Table  I.     Early  titles  of  oleoresins 

1825.  Huile  de  Fougere  Male  —  PescMer. 

1826.  Extractum    Filicis    maris    resinosum  —  Buchner. 

1827.  Extractum   oleo-resinosum   Filicis  —  Brandes. 
Oleum  Filicis  Maris    — Van  Dyk. 

Oleo-Besina  Filicis,  PescMer  —  Ver.  P.  d.  Lond.,  Edinb.  and  Dub. 
Med.  Coll. 

1828.  Oleoresine   de   Fougere   Male  —  Peschier. 
Extrait   oleoresineux  de  Cuhehe  —  Dublanc. 

1829.  Extractum  Filicis  aethereum  —  App.  to  Pruss.  P. 
Aetherisches  FamJcrautextract  —  App.  to  Pruss.  P. 

1832.     Extractum  Filicis  oleo-resinosum  —  Jourdan,  Univ.  P. 

1834.     Fiperoide  du  Gingemhre  —  Beral. 

1841.     Extractum  Eadicis  Filicis  Maris  aethereum  —  Bad.  P. 

Aetherisches  FarrnTcrautwurzel  Extract  —  Bad.  P. 

Extractum  Cuheharum  aethereum  —  Bad.  P. 

Aetherisches  Cuhehen  Extract  —  Bad.  P. 
1845.    Extractum  Filicis  Maris  aethereum  —  Geiger's  P. 

Farrnwurzelextract  —  Geiger  's  P. 

Extrait  eth^re  de  Cutehe  —  Geiger 's  P. 

Oleoresinous  Extract  of  Cuhehs  —  Bell 

Ethereal  Extract  of  Cuheis  —  Procter. 
1849.     Oleoresinous  Ethereal  Extracts  —  Procter. 
1852.    Extractum  Filicis  Maris  aethereum  —  Swiss  P. 

Extrait  oleo-r^sineux  de  Fougere  —  Swiss  P. 

Huile  de  Fougere  de  Peschier — Swiss  P. 
1854.     Extractum  Stipitum  Aspidii  —  Nor.  P. 
1857.     Oleo-Besineux  de  Cultehe  —  Garot  and  Schaeuffele. 
1859.     Oleoresina    (ae) — Procter. 
1863.     Oleoresina  Capsici  —  U.   S.  P. 

Oleoresina  Cuhehae  —  U.  S.  P. 

Oleoresina  Lupulinae  —  U.  S.  P. 

Oleoresina  Piperis  —  U.  S.  P. 

Oleoresina  Zingiberis  —  U.   S.   P. 

As  becomes  apparent  from  the  preceding  table,  oleoresins  be- 
came a  recognized  class  of  galenical  preparations  with  their  in- 
troduction into  the  United  States  PJiarmacopma  of  1860.  The 
name,  as  applied  to  a  class  of  galenicals,  appears  to  have  been  sug- 
gested by  Procter  in  1846.  Although  this  term  thereby  ac- 
quired a  dual  meaning,^)  it  was  not  only  shorter,  but  in  other 
respects  more  convenient  than  extracta  aetherea,  previously  in 
use  in  some  of  the  European  pharmacopoeias.      The  disadvan-. 


^As  a  class  of  natural  plant  products  and  as  a  class  of  galenicals. 


HISTORICAL.  INTRODUCTION.  Q 

tage  accruing  from  the  substitution  of  oleoresina  for  extracta 
uetherea  lay  in  the  fact  that  as  a  sub-class  they  were  removed 
from  the  other  sub-classes  of  extracts :  e.  g.,  the  extracta  (solida)^ 
extracta  fluida,  etc.  With  the  substitution  of  acetone  for  ether 
as  an  extracting  medium,  in  the  eighth  revision  of  the  United 
States  Pharmacopoeia,  it  is  possibly  fortunate  that  the  designa- 
tion extracta  aetherea  never  gained  a  footing  in  this  country. 

The  preparation  of  this  particular  class  of  galenicals  was  de- 
pendent upon  the  use  of  ether.  Although,  a  number  of  chem- 
ists before  the  eighteenth  century  had  obtained  some  ether  as  an 
ingredient  of  a  mixture  resulting  from  the  action  of  sulphuric 
acid  upon  alcohol,  it  appears  that  the  first  commercial  ether 
was  prepared  in  1730  by  Frobenius,^)  who,  however,  kept  his 
process  a  secret.  The  use  of  the  distillation  residues  for  the 
preparation  of  more  ether,  known  to  Frobenius,  was  emphasized 
by  several  German  chemists,  and  caused  a  considerable  reduc- 
tion in  the  price  of  this  article.  Thus  Cadet,  in  1774,  pointed 
out  that  he  could  sell  an  ounce  of  ether  at  40  sous,^)  whereas 
Baume  had  sold  it  at  12  livres.  But  even  with  this  reduction 
in  price,  ether  does  not  appear  to  have  been  a  common  phar- 
maceutical commodity  at  that  time.  Thus,  e.  g.,  Hermbstaedt^) 
in  1792,  mentions  ether  and  enumerates  its  properties  evidently 
for  the  reason  that  it  is  of  pharmaceutical  interest  primarily  be- 
cause it  is  an  ingredient  of  Liquor  anodynus  mineralis  Hoff- 
manni.  However,  it  should  be  remarked  that  Baume  mentioned 
it  in  1762  as  a  solvent  in  the  preparation  of  resin  of  Jalap,*)  and 
in  1790,^)  he  described  its  use  in  the  preparation  of  ethereal, 
tinctures. 

The  first  positive  reference  concerning  the  use  of  ether  as  a 
solvent  in  the  preparation  of  a  galenical  of  the  type  of  our  pres- 
ent oleoresins,  that  appears  in  the  literature,  is  to  be  found  in 
Peschier's  report  (in  1825)  on  the  preparation  of  the  Huile  de 
Fougere  Male,  the  present  oleoresin  of  aspidium.  As  a  result 
of  the  almost  immediate  popularity  of  this  preparation,  other 
pharmacists  were  induced  to  experiment  with  ether  in  attempting 
duplicate  or  modify  Peschier's  process.      However,  none  of  the 


^Kopp.   Geschicht.  d.  Chem,,  vol.  4,  p.  302. 

2  Ibid. 

3  Grundriss  d.  exp.  Pharm.,  part  2,  p.  161. 
♦Elements  de  Pharm.    (1872),  p.   284. 
•Ibid.   (1790),  p.  262. 


IQ  DU  MEZ— THE  GALENICAL.  OLEORESINS 

early  workers  attempted  to  employ  it  in  the  extraction  of  other 
plant  drugs,  and  it  was  not  until  1834,  when  Beral  again  called 
attention  to  the  use  of  ether  as  a  solvent  in  his  preparation  of 
Piperoide  du  Gingemhre,  our  present  oleoresin  of  ginger,  that 
its  value  in  the  extraction  of  oleoresinous  drugs  appears  to  have 
been  recognized.  From  then  on,  however,  its  use  seems  to  have 
widened  rapidly  as  the  French  Pharmacopoeia  of  1839  contained 
no  less  than  nineteen  ethereal  tinctures.  The  increase  in  the 
number  of  oleoresins  was  not  as  rapid  as  might  be  expected  in 
view  of  the  statement  concerning  the  ethereal  tinctures.  Only 
two  other  members  of  this  class  of  preparations  made  their  ap- 
appearance  before  1850,  namely,  the  Extractum  Cxihehariim 
aethereum  and  the  Extractum  Seminis  Cinae  aefhereum. 

Some  idea  of  the  rate  at  which  the  Extracta  aetJierae,  our  pres- 
ent oleoresins,  came  into  existence  and  were  given  official  recog- 
nition will  become  evident  from  the  following : 

In  the  Prussian  Pharmacopoeia  of  1829,  but  one  such  prepara> 
tion  was  official,  namely, 

Extractum  Filicis  aethereum. 


The  Baden  Pharmacopoeia  of  1841  contained  three  prepara- 
tions of  this  class,  viz: 

1.)     Extractum  Badicis  Filicis  Maris  aethereum. 
2.)     Extractum  Cuheharum  aethereum. 
3.)     Extractum  Seminis  Cinae  aethereum. 


The  Danish  Pharmacopoeia  of  1850  contained  two  prepara- 
tions of  this  class,  viz: 

1.)     Extractum  Cuheharum  aethereum. 
2.)     Extractum  Filicis  Maris  aethereum. 


The  third  edition  of  the  United  States  Pharmacopoeia,  which 
appeared  in  1851,  included  two  fluid  extracts  prepared  with 
ether  as  a  menstrum,  viz: 

1.)     Extractum  Culehae  fluidum. 
2.)     Extractum   Piper  is  fluidum. 


HISTORICAL  INTRODUCTION. 


11 


The  Belgian  Pharmacopoeia  of  1854  recognized  no  less  than 
seven  ethereal  extracts,  viz: 

1)  Extrait  etJiere  de  Fougere 

2)  Extrait  4there  de  Cantharides 

3)  Extrait  ^there  de  Croton 

4)  Extrait  ^there  de  Culjehe 

5)  Extrait  4therS  de  d'Aunee 

6)  Extrait  etMre  de  Bois  garu 

7)  Extrait  etMre  de  Semen-contra 

It  will  be  seen  from  the  above  array  of  ethereal  extracts  of- 
ficial in  European  pharmacopoeias  that  the  introduction  of 
oleoresins  into  the  fifth  edition  of  the  United  States  Pharmaco- 
poeia, which  appeared  in  1863,  was  well  prepared. 

Procter  is  commonly  given  credit  for  having  introduced  oleore- 
sins into  American  materia  medica.  That  he  was  instrumental 
in  bringing  them  to  the  attention  of  the  representatives  of  the 
regular  medical  school,  and  that  he  obtained  a  place  for  them 
in  the  United  States  PJiarmacopoeia,  possibly  no  one  has  reason 
to  doubt.  A  review  of  the  early  American  literature  on  this 
subject  not  only  reveals  this  fact,  but  it  also  brings  out  the  fact 
that  Procter  appears  to  have  been  ignorant  in  large  part  of  the 
use  of  this  class  of  preparations  in  Europe,^)  for  nowhere  does 
he  mention  it.  It  is  note-worthy  that  it  was  a  medical  prac- 
titioner (Goddard)  who  first  drew  Procter's  attention  (1846), 
not  to  a  typical  representative  of  this  class,  but  to  the  prepara- 
tion of  Dublanc  which  was  a  representative  of  the  extracta  oleo- 
resina  made  by  a  very  cumbersome  process,  now  long  discarded 
as  being  as  unscientific  as  it  is  impractical.  In  the  same  year, 
the  English  pharmacist,  Bell,  had  his  attention  drawn  to  this 
same  preparation  by  Vore,  thus  showing  that  valuable  prepara- 
tions not  advertised  were  ignored,  while  a  quasi  scientific  pre- 
paration heralded  about  apparently  attracted  general  attention. 

To    what    extent  the  Eclectic  school  of  medical  practioners 
contributed  to  the  popularization  of  this  class  of  galenicals  be- 
fore 1860  cannot  be  definitely  stated  from  the  scanty  informa- 


1  That  Proctor  did  know  of  Mohr's  work  on  this  class  of  preparations 
becomes  apparent  when  the  fact  is  recalled  that  he  adapted  Redwood's 
translation  of  Mohr's  Pharmaceutische  Technik  to  American  pharmacy  under 
the  title  of  Mohr,  Redwood  &  Procter's  Pharmacy  in  1849,  and  that  he  bad 
previously  reviewed  Redwood's  translation  in  the  Am.  Jour,  of  Pharm. 


22  DU  MBZ— THE  GALENICAL.  OLEORESINS. 

tion  at  hand.  However,  it  is  interesting  to  note  that  the 
American  Dispensatory  of  1854,  gives  the  formula  of  Robinson 
for  preparing  the  ethereal  oil  of  xanthoxylum,  the  present 
Eclectic  oleoresin  of  xanthoxylum.  The  same  is  directed  to  be 
prepared  by  extracting  the  bark  with  ether  and  subsequently 
removing  the  ether  by  evaporation — a  process  similar  to  the  one 
now  employed  in  preparing  the  official  oleoresins.  Of  but 
slightly  lesser  interest  is  the  advertisement  of  Wm.  S.  Merrel 
which  appeared  in  the  Eclectic  Medical  JournM  in  1855.  Under 
the  heading,  Class  II. — Soft  resinoids  and  oleo-resins,  etc.,  the 
following  preparations  were  listed: 

Apocynin  (from  Dogsbane). 

Ascelepedin  (from  Pleurisy  Boot), 

Aletrin  (from  Star  Koot).  ; 

^upurpurin  (from  Queen  of  the  Meadow).  I 

Iridin^  (from  Blue  Flag). 

Ptelein,  or  Oil  of  Ptelea  (from  Water  Ash). 

Oil  of  Lohelia  (from  Lobelia  Seed). 

Oil  of  Xanthoxylum  (from  Prickley  Ash). 

Oil  of  Capsicum  (from  African  Cayenne).  i 

Oil  of  Stillingia  .^p^ 

Oil  of  Male  Fern 


In  view  of  the  fact  that  these  preparations  were  already  being 
manufactured  and  advertised  commercially  in  1855,  there  can  be 
but  little  doubt  that  the  Pharmacopoeial  Revision  Committee  of 
1860  must  have  been  aware  of  their  existence  and  have  been  in- 
fluenced to  some  extent  thereby. 

Definition 

Oleoresins,  as  a  class  of  galencials,  are  extracts  prepared,  as 
a  rule,  with  the  aid  of  a  highly  selective  solvent.  Ether  is  the 
solvent  usually  employed  for  this  purpose  at  the  present  time, 
whereas,  acetone  was  directed  to  be  used  in  the  eighth  revised 
edition  of  the  United  States  PJiarmacopma.  Other  solvents  of 
this  nature,  namely:  petroleum  ether,  benzene,  chloroform,  car- 
bon tetrachloride,  et  cetera,  have  been  used,  but  have  not  been 
ofQcially  recognized.       The  oleoresin  of  cubeb  is  an  exception 


-  Prof.  John  King  is  said  to  have  prepared  and  used  Irisin   ( identical  with 
Iridin)  in  1844.     Letter  from  J.  U.  Lloyd  to  Edward  Kremers   (1906). 


DEFINITION  13 

to  the  rule  as  alcohol  is  the  menstruum  directed  to  be  used 
in  its  preparation. 

These   preparations    derive   their   name   from   the  fact  that 
the    drugs    from    which   they    were    originally    prepared    con- 
tained appreciable  amounts  of  fatty  or  volatile  oil  and  resin, 
substances,   for  which  ether  and  acetone  were   recognized  to 
be  good  solvents.      They  do  not  by  any  means  necessarily  cor- 
respond to  the  so-called  natural  oleoresins,  which  consist  for 
the  main   part   of  volatile   oil   and   resin;   but,  in  some  cases, 
are  products  relatively  poor  in  one  or  both  of  these  constit- 
uents.     Thus,  for  example,  the  oleoresin  of  capsicum  contains 
little   or  no  volatile  oil   and   only  a  small  amount  of    resin, 
while    the    oleoresin    of    parsely  is  practically  free  from  resin. 
Furthermore,  these  preparations  are  not  always  liquid  as  is  gen- 
erally stated.      The  oleoresin  of  lupulin,  for  instance,  is  of  the 
consistence  of  a  soft  extract  when  prepared  according  to  phar- 
macopoeial    directions,    and    tends    to  become  firmer  with  age 
owing  to  the  transformation  of  the  so-called  soft  into  hard  resin. 
The  manner  in  which  the  oleoresins  have  been  defined  in  the 
various  text  books  and  treatises  on  pharmacy  is  brought  out  by 
the  following  examples,  which  are  representative  of  the  periods 
corresponding  to  the  different  decennial  revisions  of  the  United 
States  PJiarmacopoeia: 

"Oleoresinae  —  Their  peculiarity  is  that  they  consist  of  principles  which 
when  extracted  by  means  of  ether,  retain  a  liquid  or  semi-liquid  state 
upon  the  evaporation  of  the  menstruum,  and  at  the  same  time  have  the 
property  of  self-preservation,  differing  in  this  respect  from  the  fluid  ex- 
tracts which  require  the  presence  of  alcohol  to  prevent  decomposition. 
They  consist  chiefly,  as  their  name  implies,  of  oil,  whether  fixed  or  volatile, 
holding  resin  and  sometimes  other  active  matter  in  solution.*'  V.  S.  Disp. 
(1870),  p.  1315. 

"  Oleoresinae,  Oleoresins  —  Mixtures  of  volatile  oils  with  resins  prepared 
by  exhausting  certain  drugs  containing  both  together,  the  menstruum  be- 
ing usually  ether  which  extracts  both.  The  menstruum  or  solvent  is  evap- 
orated off,  and  the  usually  semi-liquid  extract  which  remains  constitutes 
the  oleo-resin.*'      Oldberg  and  Wall,  C&mp.  to  the  Z7.  S.  P.  (1884),  p.  721. 

**The  oleoresins  are  official  liquid  preparations,  consisting  principally 
of  natural  oils  and  resins  extracted  from  vegetable  substances  by  per- 
colation with  ethylic  ether.  The  oleoresins  were  formerly  classed  with 
the  fluid  extracts,  but  they  differ  essentially  from  the  latter: 

1.  They  do  not  bear  any  uniform  relation  to  the  drug  as  fluid  ex- 
tracts do,  of  gramme  to  cubic  centimeter, — the  yield  of  oleoresin  obtained 


14  DU  MEZ— THE  GALENICAL,  OLEORESINS 

from  the  drug  varying  according  to  the  proportion  of  oil  and  resin  naturally 
present : 

2.  The  menstruum  used,  ethylic  ether,  extracts  principles  which  are 
often  insoluble  in  alcohol  or  diluted  alcohol,  and  vice  versa.  Oleoresin  of 
Cubeb,  for  instance,  is  not  identical  with  Fluid  Extract  of  Cubeb: 

3.  They  are  without  exception  the  most  concentrated  liquid  prepara- 
tions of  the  drugs  that  are  produced.^'  Kemington,  Pract.  of  Pharm. 
(1894),  p.  433. 

''Oleoresins  are  those  substances  obtained  from  vegetable  medicines  by 
means  of  ether  (sometimes  alcohol,  etc.,)  which  consist  principally  of  a 
fixed  or  volatile  oil  and  a  resin.  In  some  cases  the  resin  will  be  held  in 
solution  by  the  oil,  while  in  other  cases,  it  will  be  precipitated  upon  stand- 
ing and  will  require  agitation  to  diffuse  and  suspend  it  in  the  oil.  A 
third  case  occurs  in  which  the  oil  and  resin  form  a  more  or  less  perman- 
ent mixture,  having  the  consistency  of  a  very  soft  extract."  King's  Am. 
Disp.  (1900),  p.  1330. 

"Oleoresins  are  ethereal  extracts  of  an  oleoresinous  nature,  obtained 
from  vegetable  drugs  by  percolation  with  ether."  Coblenz's  EandbooJc  of 
Pharm.   (1902),  p.  290. 

' '  Oleoresins,  Oleoresinae  (Oleoresins,  L.  oleum,  oil  and  resina,  resin) — 
Natural  solutions  of  resin  in  volatile  oils,  extracted  by  ether,  acetone  or 
alcohol."       Culbreth,  Mat.  Med.    (1906),  p.  20. 

"The  pharmaceutical  oleoresins  are  liquid  preparations  of  drugs  con- 
taining volatile  oil  and  resin,  obtained  by  percolation  of  such  drug  with 
acetone,  ether,  or  alcohol,  and  subsequent  distillation  of  the  solvent  from 
the  dissolved  oleoresins."     Arny,  Prin.  of  Pharm.     (1909),  p.  259. 

"Solutions  of  this  class  represent  the  medicinal  virtues  of  the  drugs 
from  which  they  are  made,  in  a  more  concentrated  form  than  is  possible 
•in  any  other.  They  possess  the  power  of  self-preservation,  and  in  this 
respect  are  superior  to  fluidextracts.  Oleoresins  consist  chiefly  of  fixed 
or  volatile  oils  associated  with  resin  and  other  constituents;  those  of- 
ficially recognized,  with  one"  exception,  are  all  prepared,  "  et  cetera. 
Caspari,   Treat,  on  Pharm.     (1916).    p.  354. 


Drugs  Used,   Their  Collection,  Preservation,  Etc. 

Since  the  oleoresins  are  characterized  chiefly  by  their  content 
of  oil  and  resin  (see  definition  above),  it  is  evident  that  they 
may  be  prepared  from  many  of  the  numerous  vegetable  drugs) 
'of  which  these  substances  constitute  an  appreciable  part.  The 
number  of  such  drugs,  however,  which  has  actually  been  used 
for  this  purpose,  is  comparatively  small  as  is  shown  in  the 
table  which  follows.  The  table  also  reveals  the  fact  that  nearly 
all  of  these  drugs  are  derived  from  phenogamous  plants  and 
that  they  consist,  as  a  rule,  of  those  organs  in  which  oils  and 
resins  are  usually  present  in  the  greatest  abundance. 


SOLVENTS  USED  15 

Tablk  2 — Drufis  from  which  oleoresias  have  been  prepared. 

Phenogams 

Alkanet  (root)  Cypripedium  (rhizome)         Pepo  (seed) 

Anacardium  (fruit)  Eucalyptus  (leaf)  Pepper  (fruit) 

Annatto  (seed)  Galan^al  (rhizome)  Pomegranate  (root) 

Asarum  (root)  Ginger  (rhizome)  Ptelea  (bark) 

Capsicum  (fruit)  Helenium  (flower)  Pyrelhrum  (root) 

Cardamon  (seed)  Iris  (rhizome)  Sabal  (fruit) 

Chenopodium  (fruit)  Kousso  (flower)  Santonica  (unexp.   flower) 

Clove  (unexp.  flower)  Lobelia  (seed)  Savine  (leaf) 

Conium  (leaf)  Lupulin  (strobile)  Senecio  (root  &  herb) 

Croton  (seed)  Matico(leaf)  Spiraea  (herb) 

Cubeb  (fruit)  Mezereum  (bark)  Taxus  (leaves) 

Parsley  (fruit)  Xanthoxylum  (bark) 

Cryptogams 
Aspidium  (rhizome)  Ergot  (sclerotium  of  Claviceps  purpurea) 

Of  the  total  immber  of  drugs  enumerated  above,  seven  have 
been  utilized  in  the  preparation  of  the  oleoresins  official  in  the 
United  States  Pharmacopoeia,  namely : 

Aspidium  Ginger  Paisley 

Capsicum  Lupulin  Pepper 

Cubeb 

With  respect  to  the  collection  (harvesting)  of  the  foregoing 
and  their  preparation  for  use,  there  is  little  of  a  general  nature 
to  be  said  as  the  plants  from  which  these  drugs  are  obtained 
differ  so  widely  in  their  habits.  This  subject  will,  therefore, 
not  be  given  consideration  here,  but  will  be  discussed  in  Part  II 
under  tlic  treatment  of  the  individual  preparations. 

Solvents  Used. 

At  the  present  time,  ether  is  the  .solvent  directed  to  be  em- 
ployed in  the  preparation  of  the  official  oleoresins  with  the  ex- 
ception of  the  oleoresin  of  cubeb  which  is  prepared  with  alcohol. 
It  will  be  recalled  that  the  first  of  this  class  of  preparations  to 
make  its  appearance,  namely,  the  Huile  de  Fougere  ofPeschier, 
was  also  prepared  with  ether.  In  fact,  ether  appears  to  have 
been  the  only  solvent^)  given  consideration  in  this  connection 
by  the  early  European  investigators. 

*  One  animal  drug,  cantharides,  has  been  utilized  for  the  preparation  of 
an  ethereal  extract.  This  preparation,  which  was  official  in  the  Belgian 
Pharmacopoeia  of  1854,  cannot  properly  be  classed  with  the  oleoresins  since 
it  contained  no  resin — the  animal  organism  being  free  from  constituents  of 
this  nature. 

2  Buchner  in  1826  experimented  with  alcohol  in  preparing  the  Extractum 
Filicis  resinosum,  while  Brandes,  in  1827,  made  use  of  a  menstrum  con- 
taining both  alcohol  and  ether,  namely  the  Liquor  anodynus,  for  the  same 
purpose.  •  Later,  1828,  Dublanc  and  Oberdoerffer  employed  alcohol  In  th« 
preparation    of   the  oleoresinous   extract  of  cubeb. 


1g  DU  MEZ— THE  GALENICAL*  OLJE30RESINS. 

With  the  introduction  of  the  oleoresins  into  the  United  States 
PJiarmacopma  of  1860,  and  their  extensive  use  in  this  country,, 
a  number  of  American  pharmacists  were  lead  to  the  conducting- 
of  experiments,  which  had  for  their  main  object  the  discovery  of 
a  solvent  less  expensive  and  less  dangerous  to  handle  than  ether. 
We  must,  however,  note  that  prior  to  this  time  (1860)  an  at- 
tempt was  made  by  Berjot,  a  Frenchman,  to  use  carbon  disul- 
phide  for  the  purpose  of  preparing  the  Extrait  olea-resineux  de 
Cuhehe.  Garot  and  Schaeuffele,  in  1857,  in  a  paper  on  Berjot 's 
preparation  showed  that  nothing  was  gained  by  its  use,  as  two 
and  one-half  times  as  much  carbon  disulphide  as  ether  was  re-' 
quired  to  extract  the  drug.  Furthermore,  the  removal  of  the 
last  traces  of  this  solvent  was  a  matter  of  considerable  difficulty. 

The  solvent  which  first  appears  to  have  suggested  itself  to 
American  investigators  was  benzin  as  is  indicated  in  the  publi- 
cations of  Procter,  Maish,  Trimble  and  others.  The  first  ac- 
count of  its  use  in  this  connection  appeared  in  1866,  when 
Procter  published  his  results  on  the  preparation  of  the  oleoresin 
of  cubeb.  The  following  table  shows  the  relative  value  of  alco- 
hol, benzin  and  ether  for  the  extraction  of  cubeb  as  found  by 
Procter. 

Table  3. — Yield  of  oleoresin  of  cubeb. 


Quantity  of  drugr 

Menstruum 

Total  Yield 

grains 

1000 

Alcohol           ...  . 

grains 
250 

1000 

170 

1000 

Ether 

'£19 

While  Procter  could  find  no  objection  to  the  use  of  alcohol  as 
a  solvent  in  the  preparation  of  this  oleoresin,  he  advised  against 
the  use  of  benzin  as  he  stated  that  it  did  not  extract  the  cubebin 
completely. 

Simultaneously  with  the  above  publication  of  Procter,  there 
appeared  an  account  of  a  general  method  for  preparing  the 
oleoresins  by  Rittenhouse.  The  latter  also  worked  with  benzin, 
but  employed  it  as  a  ''follow  up"  solvent  after  percolation  had 
been  partially  completed  with  ether.  He  also  experimented 
with  glycerin  and  fusel  oil,  employing  them  in  a  similar  manner. 

In  1872  Maish  published  a  review  of  the  experiments  of  A.  H. 


SOLVENTS  USED 


17 


Bolton  and  M.  Koth.  The  latter  of  these  two  men  conducted 
an  investigation  on  the  extraction  of  ginger  and  cubebs  with 
benzin,  the  former  also  included  capsicum  in  his  series  of  ex- 
periments. These  workers  found  that  ether  still  extracted 
some  non-volatile  matter  after  the  drugs  had  presumably  been 
exhausted  with  benzin.  Further,  that,  while  the  benzin  oleore- 
sins  were  all  soluble  in  ether,  the  ethereal  uleoresins  of  cubeb 
and  ginger  were  only  partially  soluble  in  benzin,  thus  confirming 
Procter 's  work  in  1866  on  the  oleoresin  of  cubeb. 

Henry  Trimble  was  the  next  investigator^)  to  experiment  to 
any  considerable  extent  with  benzin  as  a  solvent.  In  his  re- 
port to  the  Pennsylvania  Pharmaceutical  Association,  in  1888, 
on  commercial  oleoresins,  he  stated  that  while  benzin  was  in  his 
opinion  preferable  to  concentrated  ether  for  the  extraction  of 
capsicum,  it  would  not  answer  for  the  other  official  oleoresins. 
Following  h  a  table  showing  the  comparative  extractive  powers 
of  ether  and  benzin  as  compiled  by  Trimble : 

Table  4 — Itelatixe  extractive  power  of  benzin  and  ether. 


Drugr 


Aspidium 
Capsicum, 
Cubeb  . . . . 
Lupulin.. 
Pepper — 
Ginger — 


Yield  witli 
etiier 


Percent. 

6.51 

19.5 

21.26 

60.59 

8  79 

3.97 


Yield  with 
benzin 


Percent 
5.? 

18.1-3 

16.65 
7.04 

2.80 
2.48 


Results  similar  to  the  above  with  respect  to  the  oleoresins  of 
ginger  were  reported  by  Samuel  J.  Riegel  in  1891. 

About  this  time  George  M.  Beringer  became  interested  in  the 
preparation  of  the  oleoresins,  and  in  1892,  he  published  an  ac- 
count of  his  researches,  in  which  he  had  employed  not  only 
ether  and  benzin  as  extracting  menstrua,  but  also  the  heretofore 
little  used  solvent,  acetone.  With  respect  to  benzin,  he  ar- 
rived at  the  same  conclusions  as  did  Trimble,  viz:  that  its  use 


1  In  1877,  L.  Wolff  in  an  article  entitled:  The  use  of  Petroleum  Benzine! 
in  Pharmacy,  stated  that  benzin  extracted  none  of  the  pungent  resin  from 
ginger,  no  cubebic  acid  from  cubeb,  no  piperin  from  pepper  and  no  san- 
tonin or  resin  from  wormseed. 


18 


DU  MEZ— THE  GALENICAL.  0KE30RESINS 


is  not  permissable  in  the  preparation  of  the  official  oleoresins^), 
except,  perhaps  in  the  case  of  capsicum,  and  then  only  under 
certain  restrictions,  namely:  that  percolation  be  terminated 
after  2  cubic  centimeters  of  percolate  are  obtained  for  every 
gram  of  the  drug,  as  upon  further  percolation,  the  oleoresin  be- 
comes almost  solid  owing  to  the  large  increase  of  palmitin  ex- 
tracted. In  his  experiments  with  acetone^)  he  found  that,  as 
with  ether,  the  first  portion  of  the  percolate  contained  nearly 
all  the  medicinal  ingredients  of  the  drug.  He,  however, 
continued  percolation  until  the  drug  was  exhausted.  The 
marc  was  then  removed  from  the  percolator,  dried  and  re- 
percolated  with  stronger  ether;  but  except  in  the  case  of 
capsicum  no  further  extractive  matter  was  obtained.  The 
oleoresins  were  stated  to  be  of  excellent  quality  and  the 
yield  and  properties  were  nearly  the  same  as  when  ether 
was  used.  ■  He  especially  recommended  the  use  of  acetone  in 
preparing  the  oleoresin  of  ginger,  as  he  claimed  that  it  was  in 
every  way  equal  to  the  preparation  made  with  ether.  Follow- 
ing is  a  table  showing  Beringer's  results  with  acetone  as  com- 
pared with  ether  and  benzin : 

Table  5 — Relative  extractive  values  of  acetone,  ether  and  benzin. 


Yield  to  acetone 

Yield  to  ether 

Yield  to  benzin 

Drug 

U.S.  P. 
method 

Complete 
exhaus- 
tion 

U.  S.  P. 
method 

Complete 
exhaus- 
tion 

U.S.  P. 
metliod 

Complete 
exhaus- 
tion 

Percent. 

Percent. 

18.00 
25.00 
25.00 
24.10 
21.75 
5.57 
71.00 
24.00'^ 
5.93to9.97  3 

Per  cent. 

Percent. 

Per  cent. 
16.18 
21.00' 

Per  cent. 

Capsicum 

18.00' 

17.32 

25  00 

Cubeb 

Cubeb 

Cubeb 

1... 

Lupulin 



70.80 

Parsley 

22.30 

5.00  to  6.70 

'  Two  cubic  centimeters  of  percolate  were  collected  tor  each  grram  of  druer. 
'^Represents  total  extract  from  which  3  per  cent,  of  wax  precipitated,  leaving 
21.00  percent,  of  oleoresin. 

3  Represents  total  extract  whicii  yielded  5.93  per  cent,  of  oleoresin. 


^  Pile  (1867)  confirms  this  statement  in  so  far  as  it  concerns  the  oleoresin 
of  g-inger.  He  states  that  neither  benzin  nor  ether  completely  extract  ginger, 
but  that  alcohol  is  the   best  solvent  for  this  purpose. 

2  The  acetone  used  by  Beringer  was  procured  from  manufacturers  of 
chloroform  as  the  product  obtained  from  the  distillation  of  wood  was  found 
to  consist  largely  of  methyl  alcohol  and  even  higher  boiling  fraction.*?. 


'  SOLVENTS  USED  19 

From  a  comparison  of  the  above  data  with  those  obtained  by 
Trimble  (See  table  4),  it  would  appear  that  acetone  is  equally 
as  serviceable  as  ether  in  the  preparation  of  the  official  oleo- 
resins.  Such  appears,  also,  to  have  been  the  opinion  of  the  Re- 
vision Committee  of  the  United  States  Pharmacopoeia  of  1900, 
as  the  edition,  which  became  official  in  1905,  directed  that  acetone 
be  employed  in  the  manufacture  of  those  oleoresins  which  were 
formerly  required  to  be  prepared  with  ether.^  That  this  change 
was  unsatisfactory  is  evidenced  by  the  numerous  comments 
on  the  subject  occurring  in  the  literature,  and  by  the  fact  that 
ether  is  again  directed  to  be  used  for  this  purpose  in  the  ninth 
revised  edition  of  the  United  States  Fliarmacopoeia. 

To  those  unacquainted  with  the  situation,  the  above  action  of 
the  Revision  Committee  of  1910,  might  be  taken  to  indicate  that 
the  matter  of  the  proper  solvent  to  be  employed  in  the  manu- 
facture of  these  preparations  has  been  definitely  settled  and  the 
superiority  of  ether  in  this  respect  firmly  established.  A  close 
inspection  of  the  preceding  reports,  along  with  other  informa- 
tion of  a  similar  nature  occuring  in  the  literature,  would,,  how- 
ever, appear  to  point  out,  that,  as  in  the  case  of  the  oleoresin  of 
cubeb,  other  solvents  might  be  advantageously  employed  in  the 
preparation  of  certain  of  these  individuals.  In  this  connection 
the  use  of  benzin,^)  or  better,  petroleum  ether,^)  in  the  prepara- 
tion of  the  oleoresins  of  capsicum  and  parsley  fruit  might  be 
mentioned,  or  the  employment  of  acetone  in  the  preparation  of 
the  oleoresin  of  ginger..*)  As  further  evidence  of  the  possibil- 
ities along  this  line,  attention  is  also  called  to  the  experiments 
of  WoUenweber  (1906)  on  the  extraction  of  aspidium  with  ben- 
zene, and  to  the  mention  of  chloroform^)  and  carbon  tetra- 
chloride^) as  solvents  for  the  preparation  of  the  oleoresins  m 
general. 

The  manner  in  which  these  solvents  have  been  employed  in 


^  The  most  important  factor  in  determining  this  change  was  probably  the 
difference  in  cost  of  the  two  solvents  at  the  time  (1900),  acetone  being  the 
cheaper.  This  statement  is  confirmed  in  a  measure  by  the  fact  that  now, 
since  the  price  of  ether  has  been  reduced,  owing  to  its  preparation  from 
denatured  alcohol,   it   is   again   the   solvent  officially  recognized. 

2  See  preceding  reports  by  Trimble,  Beringer  and  others. 

^Hyers    (1895)   also  made  use  of  petroleum   ether  in  extracting  cubeb. 

*Idris  (1898)  stated  that  he  found  acetone,  b.  p.  65"  C,  to  be  the  most 
suitable  solvent  for  extracting  ginger. 

«Dorvault,  L'Officine  (1898),  p.  591. 

"Lucas,  Practical  Pharmacy  (1908),  p.  149. 


20  I>U  MEZ— THE  GAUSNICAX.  OLEORESINS. 

the  preparation  of  the  various  oleoresins  will  be  discussed  in 
a  general  way  under  methods  of  preparation  and  in  detail  under 
individual  oleoresins. 

Methods  of  Preparation 

The  methods  of  preparing  the  oleoresins  as  outlined  in  the 
present  edition  of  the  United  States  PJiarmacopoeia  may  be 
stated  in  the  following  general  way:  extract  the  drug  com- 
pletely^) by  percolation,  expose  the  percolate  in  a  warm  place 
until  the  solvent  has  completely  evaporated  and  separate  the 
remaining  liquid  portion  from  any  deposited  material.  This  is 
essentially  the  method  of  procedure  given  in  most  of  the  late 
editions  of  the  foreign  pharmacopoeias  as  well,  notable  excep- 
tions being  the  German  and  Japanese.  In  the  two  latter,  the 
drug  is  directed  to  be  exhausted  by  maceration  instead  of  per- 
colation. In  detail,  the  methods  described  in  the  United  States 
Pharmacopoeia,  as  well  as  the  foreign  pharmacopoeias,  differ 
somewhat  Avith  the  particular  oleoresin  as  will  be  brought  out  to 
some  extent  in  the  following  discussion  and  more  minutely 
under  the  separate  treatment  of  each  individual.  It  is  perhaps 
needless  to  state  that  these  methods  are  not  of  recent  invention 
but  have  been  gradually  evolved  from  the  numerous  experiments 
conducted  both  in  this  country  and  abroad. 

The  first  of  these  experiments  dates  back  to  the  year  1825, 
when  Peschier  prepared  the  Huile  de  Fougere  Male,  our  pres- 
ent oleoresin  of  aspidium.  In  his  description  of  the  method  of 
preparation,  he  directs  that  the  male  fern  rhizomes  be  extracted 
with  successive  portions  of  ether,  the  decanted  ethereal  solu- 
tions mixed  and  evaporated  at  a  gentle  heat,  and  the  remaining 
oily  residue  collected  and  preserved  as  the  finished  product. 
This  is  essentially  the  method  which  appeared  in  the  early 
European  pharmacopoeias  as  is  shown  in  the  following  typical 
example  taken  from  the  Prussian  Pharmacopoeia  of  1830 : 

Agitate  one  ounce  of  powdered  male  fern  root  with  successive  portions 
of  eight  ounces  of  ether  until  the  ether  decants  clear.  Then  mix  the 
several  portions  and  strain.  Distill  down  to  one-fourth  of  the  volume 
and  evaporate  the  remainder  on  a  water   bath  to  a  thin  yellowish-brown 

extract. 


1  Percolation,  in  the  extraction  of  capsicum  is  directed  to  be  discontinued 
when  eight  hundred  mills  of  percolate  have  been  obtained. 


METHODS  OF  PREPARATION  21 

An  inspection  of  the  above  method  brings  out  the  fact  that 
the  decanted  menstruum  was  directed  to  be  clarified  by  the 
process  of  straining.  Not  only  was  a  great  deal  of  the  solvent 
lost  by  evaporation  in  this  procedure,  but  a  very  considerable 
amount  remained  adhering  to  the  marc.  While  some  of  the 
latter  was,  in  actual  practice,  removed  by  pressing  the  drug 
on  the  strainer  with  the  hands,  Mohr^)  in  commenting  on  the 
method  stated  that,  inasmuch  as  three-fourths  of  the  ether  were 
■often  lost  in  these  operations,  it  was  useless  to  recover  the  re- 
mainder by  evaporation.  To  overcome  this  loss  to  some  extent, 
he  suggested  making  these  preparations  in  the  winter  when  the 
low  temperature  would  be  less  favorable  for  the  volatilization  of 
the  solvent.  As  ether,  at  this  time  and  for  many  years  later, 
was  a  comparatively  expensive  solvent,  it  will  become  apparent 
that  a  change  in  the  method  was  to  be  desired. 

The  first  decided  departure^  from  the  above  method  of  pro- 
cedure, which  appears  to  have  been  given  official  recognition,  is 
to  be  noticed  in  the  Baden  Pharmacopoeia  of  1841.  The  method 
briefly  stated  is  as  follows : 

Mix  the  powdered  male  fern  root  with  a  sufficient  quantity  of  ether  to 
thoroughly  moisten  it.  Then  extract  it  in  a  EeaVsche  Presse  so  connected 
with  a  receiving  flask  that  none  of  the  menstruum  will  be  lost  by  evap- 
oration. 

A  few  years  later,  in  1846,  there  appeared  a  method  in  the 
Swedish  Pharmacopceia  which  likewise  included  the  process  of 
displacement,  viz: 

Macerate  the  male  fern  root,  cut  in  small  pieces,  with  ether  and  extract 
in  a  displacement  apparatus.^  Then  distill  the  ethereal  solution  to  one- 
fourth  of  its  volume  and  evaporate  the  remainder  on  a  water  bath  to  the 
consistence  of  a  thin  extract. 

Even  with  the  use  of  a  pressure  percolator,  so  much  ether 
was  still  lost  through  spontaneous  evaporation  and  through  ab- 


*  Mohr,   Redwood  and   Procter's  Pharmacy    (1849),   p.   263. 

2  Geiger,  in  1827,  employed  the  Real'sche  Presse  in  the  preparation  of  the 
Oleum  Filicis  Maris,  our  present  oleoresin  of  aspidium. 

'  The  apparatus  employed  for  this  purpose  was  most  probably  the  Filtre- 
presse  of  Count  Real  or  the  Luft-presse  of  Dr.  Romershausen,  as  both  of 
these  so-called  presses  were  in  general  use  at  that  time.  In  fact,  both  are 
mentioned  in  connection  with  the  preparation  of  the  extracta  by  the  Prus- 
sian Pharmacopoeia  as  early  as  1834. 


22  DU  MEZ— THE  GALENICAL  OLEORESINS 

sorption  by  the  bag/)  that,  in  operating  with  small  quantities 
of  the  drug,  the  recovery  of  the  remainder  was  scarcely  worth 
the  trouble.  The  recognition  of  these  defects  by  Mohr  lead 
him  to  construct  (in  1847)  a  special  form  of  apparatus  for  con- 
tinuous extraction  with  volatile  solvents.  However,  while 
Mohr 's  apparatus  was  a  success  from  an  economical  standpoint,, 
there  is  no  evidence  to  show  that  it  was  ever  employed  to  any 
extent  by  the  American  pharmacist,  although,  Procter,  the 
American  editor  of  Kedwood's  translation  of  Mohr's  treatise 
on  pharmacy,  advocated  its  use  in  this  connection  in  1849. 

About  this  time  (1846)  Procter  caused  the  American  pharma- 
cists to  become  interested  in  this  class  of  preparations  by  call- 
ing attention  to  his  improvement  upon  Soubeiran's  method  (as 
suggested  by  Dublanc)^)  for  preparing  the  Extrait  oleo-resineux 
de  CuhehCf  a  preparation  similar  to  our  present  oleoresin  of 
cubeb.      The  following  is  the  method  as  devised  by  Procter. 

"Take  cubebs,  in  powder,  one  pound  avoirdupois,  and  sulphuric  ether 
a  sufficient  quantity,  which  is  two  and  one-half  to  three  pounds;  intro- 
duce the  powder  into  a  displacer,  insert  the  lower  end  into  a  bottle  that 
fits  it,  add  the  ether  carefully,  and  cover  the  top  of  the  filter  with  a 
piece  of  wet  bladder  through  which  several  pin  holes  have  been  made.'  The 
flow  should  be  very  gradual  and  if  too  rapid,  the  filter  should  be  partially 
closed  with  a  cork.  By  attention  to  this  point,  much  less  ether  will  be 
required.  The  ethereal  tincture  should  be  introduced  into  a  large  retort^ 
heated  by  a  water  bath,  and  the  receiver  well  refrigerated.  The  dis- 
tillation should  not  be  hurried  toward  the  last.  When  five-sixths  of  the 
ether  have  passed,  it  should  be  separated  for  use,  and  the  evaporation  be 
continued  in  the  retort,  observing  to  keep  the  temperature  below  120®F, 
so  as  not  to  volatilize  the  volatile  oil.'* 

A  few  years  later  (1850),  this  method  (in  essential  detail) 
was  given  recognition  by  the  United  States  Pharmacopma  in 
connection  with  the  preparation  of  the  fluid  extracts  of  cubeb 
and  pepper,  later  known  as  the  oleoresins  of  cubeb  and  pepper, 
respectively.       For    the    purpose  of  better  bringing  out  this 


»  Mohr,  Redwood  and  Procter's  Pharmacy  (1845),  p.  263. 

^Although  Dublanc  described  a  method  for  preparing  the  oleoreslnous 
extract  of  cubeb,  similar  to  that  of  Soubeiran,  in  1828,  neither  method  is 
given  consideration  here  as  both  differed  to  such  an  extent  from  the  usual 
procedure  that  they  had  little  or  no  influence  on  the  development  of  the 
present  process. 

«From  the  above  description,  it  appears  that  the  form  of  displacer  used 
by  Procter  was  the  one  described  in  Mohr,  Redwood  and  Procter's  Phar- 
macy,   (1849),   p.    270. 


METHODS  OF  PREPARATION  23 

similarity,  the  following  general  statement  of  the  pharmaeopoeial 
methods  is  also  given : 

Take  of  the  Drug,  in  powder,  a  poundj 

Ether  a  sufficient  quantity. 

Put  the  drug  into  a  percolator,  and  having  packed  it  carefully,  pour 
the  ether  gradually  upon  it  until  two  pints  of  filtered  liquid  are  ob- 
tained, then  distill  off  by  means  of  a  water-bath,  at  a  gentle  heat,  a  pint 
and  a  half  of  the  ether,  and  expose  the  residue  in  a  shallow  vessel,  until 
the  whole  of  the  ether  has  evaporated. 

The  methods  in  general  as  they  were  given  in  the  United 
States  Pharmacopoeia  of  1860  differ  from  the  above  only  in  the 
quantity  of  drug  and  menstruum  directed  to  be  taken.  Thus, 
twelve  troy  ounces  of  drug  were  directed  to  be  subjected  to  per- 
colation with  ether  until  twenty-four  fluidounces  of  filtered 
liquid  were  obtained,  "when  eighteen  fluidounces  of  the  ether 
were  to  be  removed  by  distillation.  In  the  preparation  of  the 
oleoresin  of  ginger,  however,  the  following  method  of  procedure 
was  given: 

"Take  of  Ginger,  in  fine  powder,  twelve  troyounces; 

"Stronger  ether  twelve  fluidounces; 

"Alcohol   a   sufficient   quantity. 

"Put  the  ginger  into  a  cylindrical  percolator,  press  it  firmly,  and  pour 
upon  it  the  stronger  ether.  When  this  has  been  absorbed  by  the  powder, 
add  alcohol  until  twelve  fluidounces  of  filtered  liquid  have  passed.  Ee- 
cover  from  this,  by  distillation  on  a  water-bath,  nine  fluid-ounces  of  ether, 
and  expose  the  residue  in  a  capsule  until  the  volatile  part  has  evaporated.'^ 

That  the  Pharmaeopoeial  Eevision  Committee  was  informed 
of  the  work  of  Beral  in  this  connection  appears  to  be  clearly 
evident,  as  it  was  he,  who  first  suggested  this  procedure  (1834), 
also,  in  the  preparation  of  the  oleoresin  of  ginger,  then  known 
as  the  Piperoide  du  Gingemhre. 

In  1866,  Kittenhouse,  commenting  on  the  methods  in  gen- 
eral, which  were  given  in  the  United  States  Pharmacopoeia  of 
1860,  stated  that  about  thirty-six  fluid  ounces  of  ether  were  re- 
quired to  extract  the  drug  when  proceeding  as  officially  directed. 
He,  however,  conceived  the  idea  of  reducing  the  amount  of  ether 
by  a  procedure  similar  to  that  employed  in  extracting  the  gin- 
ger rhizomes.  Alcohol  did  not  appeal  to  him  as  the  proper 
* 'follow  up"  solvent  for  this  purpose  and  he,  therefore,  con- 
ducted a  series  of  experiments,  in  which  he  made  use  of  benzin. 


24 


DU  MEZ — THE  GALENICAL.  OLEORESINS. 


glycerin  and  fusel  oil. 
finally  devised  by  him : 


The  following  is  the  working  formula 


''Take  any  convenient  quantity  of  the  drug;  for  each  ounce  thus  em- 
ployed, iy2  fluid  ounces  of  ether,  and  1  fluid  ounce  or  q.  s.  of  benzin. 
Pack  the  drug  in  a  suitable  apparatus,  add  the  ether,  and  when  it  has  ceased 
to  pass,  pour  on  the  benzin  in  the  proportion  of  one  fluid  ounce  for  eacli 
ounce  of  the  drug  employed  or  until  as  much  percolate  has  been  obtained 
as  equals  the  amount  of  ether  employed.  Eeeover  the  ether  by  distilla- 
tion in  the  usual  manner." 

The  process  of  Rittenhouse  does  not  appear  to  have  received 
much  attention  as  there  is  no  subsequent  mention  of  it  to  be 
found  in  the  literature. 

During  the  meantime  Procter  continued  his  work  on  the  oleo- 
resins  and  in  the  same  year  (1866),  he  pointed  out  that  prac- 
tically all  of  the  oleoresinous  material  was  to  be  found  in  the  first 
portions  of  the  percolate,  and  that  a  considerable  quantity  of 
menstruum  could  be  saved  by  discontinuing  the  operation  be- 
fore the  drug  was  completely  exhausted.  The  following  table 
compiled  by  Procter  clearly  brings  out  this  point: 


Table  6 — Yield  of  oleoresin  of  cubeb  to  ether,  alcohol  and  benzin . 


Quantity 
of  cubeb 

Solvent 

Quantity 

of  1st 
percolate 

Yield  of 
oleoresin 

Quantity 

of  2nrt 
percolate 

Yield   of 
oleoresin 

Total 
yield 

grains 
1000 

Ether 

Alcohol 

Benzin 

grains 
1000 

grains 
205 
240 
140 

grains 
1000 

2000 

grains 
14 
30 
25 

grains 
219 
250 
170 

The  effect  of  Procter's  work  is  noticed  in  the  1870  and  1880 
editions  of  the  United  States  PJiarmacopma.  Thus,  the  Phar- 
macopoeia of  1870  directed  that  twenty  instead  of  twenty-four 
fluidounces  (as  formerly  required)  of  percolate  be  collected  for 
every  twelve  troyounces  of  drug,  while  the  Pharmacopoeia  of 
1880  required  that  only  150  parts  of  percolate  be  obtained  for 
every  100  parts  of  drug  taken.  It  should  also  be  noted,  that 
in  the  1880  edition,  the  method  of  preparing  the  oleoresin  of 
ginger  was  made  to  conform  with  that  given  for  the  other  oleo- 
resins. 


METHODS   OF  PREPARATION  25 

The  United  States  Pharmacopoeia  of  1890,  directed,  that,  in 
the  preparation  of  all  of  the  official  oleoresins,  the  drug  be  com- 
pletely exhausted  by  percolation  with  ether.  The  following 
directions  for  the  preparation  of  the  oleoresin  of  cubeb  are 
typical  of  the  methods  given : 

*  *  Cubeb,  in  No.  30  powder,  500  Gm. ;   ether  a  sufficient  quantity. 

* '  Put  the  cubeb  into  a  cylindrical  glass  percolator  provided  with  a  stop- 
cock, and  arranged  with  a  cover  and  receptacle  suitable  for  volatile  liquids. 
Press  the  drug  firmly  and  percolate  slowly  with  ether,  added  in  suc- 
sive  portions,  until  the  drug  is  exhausted.  Eecover  the  greater  part 
of  the  ether,  etc." 

The  next  edition  of  the  United  States  Pharmacopoeia  (1900) 
contained  a  number  of  changes  with  respect  to  the  methods  of 
preparing  this  class  of  galenicals.  Two  new  solvents  were  in- 
troduced, namely,  acetone  and  alcohol ;  the  method  of  procedure 
was  modified  in  the  case  of  the  oleoresin  of  capsicum,  and  an 
ordinary  percolator  was  directed  to  be  used  in  the  preparation 
of  the  oleoresin  of  cubeb.  The  following  is  a  general  state- 
ment of  the  manner  in  which  the  oleoresins  of  aspidium,  ginger, 
lupulin  and  pepper  were  directed  to  be  extracted. 

Introduce  the  powdered  drug  (degree  of  fineness  specified)  into  a  cylin- 
drical glass  percolator,  provided  with  a  stop-cock,  and  arranged  with  a  cover 
and  receptacle  suitable  for  volatile  liquids.  Pack  the  powder  firmly,  and 
percolate  slowly  with  acetone,  added  in  successive  portions,  until  the  drug 
is  exhausted. 

The  method  of  extracting  the  cubeb  was  stated  as  follows : 

Introduce  the  powdered  cubeb  (degree  of  fineness  specified)  into  a 
cylindrical  glass  percolator,  pack  the  powder  firmly,  and  percolate  slowly 
with  alcohol,  added  in  successive  portions,  until  the  cubeb  is  exhausted. 

The  method  described  for  the  extraction  of  capsicum  was 
similar  in  all  respects  to  the  first  of  the  methods  given  above, 
except  that  percolation  was  directed  to  be  discontinued  when 
eight  hundred  cubic  centimeters  of  percolate  had  been  obtained. 

The  above  changes,  except  in  the  case  of  the  oleoresin  of 
cubeb^)  must  be  attributed  to  the  work  of  Beringer,  an  account 
of  which  was  published  in  1892.  Not  only  did  he  advocate 
the  use  of  acetone  in  these  preparations,  but  he  also  pointed  out 


^  It  will  be  recalled  that  Procter  in  1866  suggested  the  use  of  alcohol  in 
preparing  the  oleoresin  of  cubeb.     See  table  3,  page  922. 


26  r>U  MEIZ— THE  GALENICAL  OLEORESINS 

the  advantage  of  discontinuing  percolation  short  of  exhaustion 
in  the  case  of  capsicum. 

The  ninth  revised  edition  of  the  United  States  PJiarmacopoeia 
shows  but  one  change  in  the  method  of  preparing  the  oleoresins, 
viz:  ether  is  directed  to  be  used  in  those  cases  where  acetone  was 
employed  in  the  preceding  edition. 

From  the  foregoing  discussion,  it  becomes  apparent  that  the 
United  States  PJiarmacopoeia,  even  to  the  present  edition,  has 
consistently  adhered  to  the  process  of  simple  percolation  in  ex- 
tracting the  oleoresinous  drugs.  This  condition  not  only  ap- 
pears strange,  in  view  of  the  fact  that  modern  methods  of 
operating  with  the  volatile  solvents,  such  as  ether,  make  use  of 
some  form  of  continuous  extraction  apparatus;  but  is  thought 
to  show  a  lack  of  progress  as  well.  Maish,  in  1900,  suggested 
the  use  of  Soxhlet's  apparatus  for  this  purpose  and  pointed  out 
its  advantage,  especially  when  operating  with  small  quantities 
of  drug.  Reference  is  also  made  in  this  connection  to  similar 
forms  of  apparatus  in  most  of  the  present  day  text-books  on 
pharmacy. 

With  reference  to  the  preparation  of  the  oleoresins  on  a  com- 
mercial scale,  there  is  good  reason  to  doubt  the  employment  of 
any  of  the  heretofore  mentioned  methods.  The  method  most 
likely  in  use  at  the  present  time  is  one  similar  to  that  offi- 
cial in  the  British  PJiarmacopoeia  of  1867.  The  latter,  briefly 
stated,  is  as  follows: 

Exhaust  the  powdered  drug  by  percolation  with  alcohol,  and  distill  the 
percolate  until  a  soft  extract  is  obtained.  Treat  this  extract  with  suc- 
cessive portions  of  ether,  mix  the  ethereal  solutions  and  again  distill  off 
the  solvent,  when  the  residue  will  constitute  the  oleoresin. 

The  advantage  of  this  method  lies  in  the  fact  that  it  requires 
the  handling  of  comparatively  small  amounts  of  ether,  and 
thereby  lessens  the  danger  incurred  in  working  witK  large  quan- 
tities of  this  highly  inflammable  solvent.  The  disadvantage  is 
that  alcohol  may  not  extract  all  of  the  eother-soluble  material 
from  the  drug. 

In  the  preceding  survey,  only  the  official  oleoresins  and  their 
methods  of  preparation  have  been  considered.  There  is,  how- 
ever, a  number  of  preparations  which  have  been  classed  as 
oleoresin,  in  Parrish's  Treatise  on  Pharmacy,  and  King's 
American  Dispensatory,  although,  they  have  never  received  of- 


APPARATUS  EMPLOYED 


27 


licial  recognition.  They  are  the  so-called  Eclectic  oleoresins 
^nd  are  in  general  directed  to  be  prepared  in  the  following  man- 
ner : 

Extract  the  drug  by  percolation  with  alcohol  or  ether  and  precipitate  the 
oil  and  resin  by  pouring  the  alcoholic  or  ethereal  tincture  into  water.  Lastly, 
separate  the  product  from  the  water  by  filtration. 

Among  the  preparations  which  have  been  made  in  this  way 
are  the  following:  oleoresin  of  iris  (iridin),  oleoresin  of 
xanthoxylum,  oleoresin  of  cardamon  (oil  of  cardamon),  oleo- 
resin of  ergot,  (oil  of  ergot)  and  oleoresin  of  parsley,^)  (oil  of 
parsley). 

In  this  connection,  it  should  be  pointed  out  that  the  fore- 
going are  liquid  preparations  and  do  not  constitute  the  so-called 
resinoids,  which  are  solids,  although  prepared  in  a  similar  way. 

Apparatus  Employed. 

Under  the  two  preceding  headlines,  the  preparation  of  the 
oleoresins  has  been  discussed  from  the  standpoint  of  the  solvent 
employed  in  extracting  the  drug,  and  with  respect  to  the  method 
of  procedure.  There,  is  however,  still  another  factor  of  inter- 
est which  deserves  consideration  in  this  connection,  namely: 
the  form  of  apparatus  made  use  of. 

It  will  be  recalled  that  the  first  of  this  class  of  preparations 
to  make  its  appearance,  the  oleoresin  of  aspidium,  as  originally 
prepared,  required  the  use  of  nothing  but  a  macerating  jar, 
a  cloth  strainer  and  some  sort  of  container,  in  which  the  colated 
liquid  could  be  collected  and  exposed  to  the  air  to  permit  the 
evaporation  of  the  solvent.  Likewise,  these  were  the  utensils 
generally  employed  in  the  experimental  stages  of  the  prepara- 
tion of  the  other  members  of  this  class  which  became  known  at 
an  early  date.  As  soon,  however,  as  the  oleoresins  became 
recognized  as  regular  pharmaceutical  commodities,  the  method 
of  preparation  as  outlined  above  was  found  to  be  impractical 
owing  to  the  complete  loss  of  the  solvent  by  evaporation.  In 
adapting  the  same  to  commercial  use,  steps  were,  therefore, 
taken  to  recover  as  much  of  the  latter  as  possible.  For  this 
purpose,  some  form  of  distilling  apparatus  was  employed,  pre- 


*This   preparation   should   not  be   confused   with   the   oleoresin   of   parsley 
as  official  in  the  present  edition  of  the  United  States  PharmacopoBia. 


28 


DU  MEZ— THE  GAUENICAL.  OL.EORESINS. 


sumably,  the  retort  and  condenser.  Even  with  this  modifica- 
tion, however,  a  large  part  of  the  solvent  was  still  lost  in  the 
operation  of  straining. 

About  this  time  (1820  to  1840),  the  extraction  of  drugs  by 
the  process  of  downward  displacement  was  attracting  consider- 
able attention,  and,  as  the  pharmacist  saw  in  this  procedure  a 
means  of  eliminating  the  operation  of  straining,  it  is  not  at  all 
surprising  that  it  should  have  received  early  application  in  the 
preparation  of  the  oleoresins.  In  explanation  of  the  method  of 
procedure  as  followed  at  the  time,  it  should  be  stated  that  it  was 
in  reality  a  process  of  percolation  under  pressure,  and,  as  such, 
required  the  use  of  a  special  form  of  apparatus.  Two  such 
forms  were  already  available  at  the  time  when  the  oleoresins 
became  a  subject  for  investigation,  namely :  the  Filtre-Presse  of 
Keal  and  the  Luft-Presse  of  Romershausen.  In  fact,  Geiger 
made  use  of  the  former  in  the  preparation  of  the  oleoresin  of 
male  fern  as  early  as  1827.  While  these  forms  of  pressure 
percolators  eliminated  the  process  of  straining,  their  use,  never- 
theless, appears  to  have  been  disadvantageous  in  certain  other 
respects.  For  instance,  the  method  of  operation  was  rather 
cumbersome,  and  a  considerable  amount  of  solvent  was  absorbed 
by  the  cloth  bag  containing  the  powdered  drug,  thus  rendering 
the  apparatus  of  little  value  in  working  with  small  quantities 
of  the  latter. 

As  a  result  of  the  early  work  with  the  pressure  percolators, 
experimentation  along  this  line  was  stimulated  and  it  was  soon 
shown  that  drugs  could  be  completely  extracted  by  simple  per- 
colation under  ordinary  atmospheric  pressures.  The  first  evi- 
dence of  the  use  of  a  simple  percolator  in  the  preparation  of 
the  oleoresins  appears  in  Beral's  account  of  his  preparation  of 
the  Piperoide  du  Gingembre  in  1834.  Fifteen  years  later 
(1849),  Procter,  in  an  article  on  the  oleoresinous  ethereal  ex- 
tracts, mentioned  two  forms  of  simple  percolators,  a  conical 
percolator  made  of  tin,  and  Gilbertson's  displacement  apparatus 
constructed  of  glass.  Both  of  these  were  similar  in  essential 
detail  to  the  percolators  in  general  use  at  the  present  time.  In 
fact,  the  United  States  Pharmacopoeia  still  directs  that  these  pre- 
parations be  made  by  simple  percolation,  a  modified  form  of 
Gilbertson's  displacement  apparatus  being  specified  for  use  in 
this  connection.  This  condition  seems  strange,  indeed,  in  view 
of  the  fact  that  modern  methods    of    operating    with  volatile 


APPARATUS  EMPLOYED 


29 


solvents,  such  as  ether,  make  use  of  some  form  of  continuous  ex- 
traction apparatus. 

Such  an  apparatus  was  invented  by  Mohr  in  1847  and  its 
advantages  in  the  preparation  of  the  oleoresins  pointed  out  by 
him  at  this  time,  and  later,  by  Procter.  An  apparatus  operat- 
ing on  similar  principles  was  described  by  Parrish  in  1884  in  his 
Treatise  on  Pharmacy.  More  recently  Maish  (1900)  has  sug- 
gested the  use  of  the  Soxhlet  apparatus  for  the  preparation  of 
small  quantities  of  oleoresins,  while  a  number  of  other  forms  of 
continuous  extraction  apparatus  have  been  mentioned  in  this 
connection  in  the  various  periodicals  and  text-books  on  phar- 
macy. 

The  different  forms  of  apparatus,  which  have  been  mentioned 
at  various  times  in  connection  with  the  preparations  of  the  oleo- 
resins, and  the  methods  of  operating  with  the  same  are  described 
in  detail  in  the  following  chronological  list: 
Cadet,  C.  L. 

Filtre-presse  de  M.  Real. 

Jour,  de  Pharm.,  2,  pp.  165  and  192;  Repert.  der  Pharm.  2, 

p.  356. 


Fig.  1.)    The  body  of  the  extraction  apparatus  A  is  made  of 
tin,  the  top  of  which,  being  screwed  on,  can  be  remaved.     It  is 


30 


DU  MEZ— THE  GALENICAL  OLEORESINS 


supported  on  a  tripod.  At  D  and  D  are  two  false  bottoms  be- 
tween which  the  material  to  be  extracted  is  packed.  Into  the 
cpver  of  the  apparatus,  the  pipe  B,  which  may  be  50  to  60  feet 
high,  is  fitted.  The  communication  between  B  and  A  may  be 
stopped  by  means  of  the  stop  cock  C.  The  dish  E  under  the 
tripod  receives  the  percolate. 

Fig.  2.)  The  second  figure  is  a  modification  of  the  first  do- 
ing away  with  the  long  tube.  The  solvent  is  admitted  to  the 
space  X  by  pouring  it  into  the  funnel  E.  The  percolate  is 
collected  in  the  container  G.  The  pressure  is  secured  by  filling 
the  cast  iron  container  A  with  mercury.  After  the  apparatus 
C  is  charged  with  drug  and  solvent,  the  stop-cock  H  is  closed 
and  the  pipe  B  also  filled  with  mercury  which  then  forces  the 
menstruum  through  the  firmly  packed  drug. 


Buchner,  J.  A. 

Beschreibung  und  Abbildung  der  von 
hausen  erfundenen  Luft-presse. 
Repert.  der  Pharm.,  6,  p.  316. 


Herrn    Dr. 


1819 

Romers- 


'^.  i^JPAarma^i^    ^ 


APPARATUS  EMPLOYED 


31 


TaiM 


.£U 


The  two  twin  cylinders  B  and  C  are  mounted  on  the  support  A 
and  are  provided  with  covers  1  and  10.  On  the  support,  the 
diaphragm  3  is  placed,  covered  with  a  straining  cloth  which  is 
held  in  position  by  the  diaphragm  4  which  in  turn  is  fastened 
by  the  clamp  5.  A  third  diaphragm  6  is  used  to  covef  the  sub- 
stance to  be  extracted.  The  two  cylinders  are  united  by  the 
tube  7  provided  with  a  stop-cock.  The  lower  part  of  B  is  also 
provided  with  a  stop-cock  at  S  in  order  to  allow  the  percolate  to 
flow  out  at  9.  The  lower  section  of  C  is  converted  into  an  air 
tight  compartment  by  the  cover  11,  which  is  provided  with  an 
opening  and  stopper  at  12.  The  parts  indicated  by  13,  14,  15, 
16,  and  17  belong  to  the  suction  pump  necessary  to  create  a  va- 
cuum. The  suction  pump  is  outside  the  cylinder  and  the  per- 
colate is  not  allowed  to  collect  underneath  the  percolator  B,  but 
is  at  once  pumped  in  the  reservoir  C. 

Beindorff  1826 

Mag.  f.  d.  Pharm.,  9,  p.  185.    [Geiger,  Hanbuch   d.     Pharm. 
(1830),  p.  142]. 

The  cuts  represent  Beindorff 's  modification  of  the  Eeal 
and  Romershausen  extraction  apparatus.  It  will  be  noticed 
that  the  apparatus  in  figure  6  is  so  mounted  that  it  can  be  tipped 


32 


DU  MEZ— THE  GALENICAL  OLEORESINS. 


at  a  convenient  angle  for  filling  and  emptying.  In  figure  7,  a 
more  compact  form  of  the  apparatus  is  shown.  In  the  latter, 
the  long  tube  is  replaced  by  an  air  pump. 


These  forms  of  pressure  percolators  were  mentioned  in  con- 
nection with  the  preparation  of  the  oleoresins  by  Mohr  (1854) 
in  his  Commentary  on  the  Prussian  PJiarmacopoeia. 


APPARATUS  EMPLOYED 


Simonin 

Journ.  de  Pharm.  et  de  Chim.,  20,  p.  128. 


33 

1834 


It  is  thought  that  one  of  the  above  represents  the  form  of  per- 
colator made  use  of  by  Beral  (1834)  in  his  preparation  of  the 
Piperoide  due  Gingemhre. 


34 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Mohr  1847 

Neuer  Extractions  Apparat  fuer  Weingeist  und  Aether. 
Arch,  der  Pharm.,  100,  p.  305.  [Am.  Journ.  Pharm.,  21, 
p.  117]. 

Fig-  78.  Fig.  79. 


J e         I 

•iii 


The  apparatus  consists  of  a  two-necked  Woulf 's  bottle,  figure 
78  p,  into  the  central  mouth  of  which  the  metallic  vessel  R,  figure 
79,  is  fitted  by  means  of  a  cork.  The  vessel  R  consists  of  a  me- 
tallic cylinder  a  having  a  perforated  strainer  k  near  the  bottom 
and  terminating  with  a  funnel  neck,  to  admit  of  its  being  fitted 
into  the  Woulf 's  bottle.  This  cylinder  is  surrounded  by  a 
second  cylinder  &,  the  space  between  them  being  intended  to 
contain  either  hot  or  cold  water.  In  the  top  of  the  inner  cylin- 
der a,  a  slightly  conical  vessel  c  is  made  to  fit  air  tight,  as  shown 
in  the  drawing.  This  vessel  c  is  intended  to  be  used  as  a  con- 
densing apparatus,  and  for  this  purpose  it  is  filled  with  cold 
water.  From  the  second  or  lateral  opening  of  the  Woulf 's  bot- 
tle, a  glass  or  tin  .tube  d,  figure  78,  is  carried  to  the  upper  part  of 
the  cylinder  a,  where  it  is  inserted  as  shown  in  figure  80.  The 
cold  water  in  the  vessel  c  is  renewed  through  the  pipe  e  which 
conducts  it  to  the  bottom,  while  the  warm  water  runs  off  from 
the  top  through  the  pipe  /,  figure  79.  Hot  or  cold  water  is  re- 
newed to  the  space  between  the  two  cylinders  R.  by  the  tube 
funnel  hy  figure  78,  and  the  water  from  this  space  overfiows  inta 
g  and  is  carried  off  together  with  that  from  /.  The  tube  h  is 
inserted  through  a  perforated  cork  at  i  so  that  by  turning  the 


APPARATUS  EMPLOYED  35 

tube  downwards,  the  water  from  the  space  between  the  cylin- 
ders can  be  run  off. 

1849 


Mohr,  Redwood  and  Procter 's  Pharmacy,  p.  270. 


This  consists  of  a  conical  vessel  A  with  a  water  joint  rim  at 
the  top  into  which  the  cover  fits.  A  tube  D  is  ground  to  fit  into 
the  opening  in  the  bottom,  and  over  the  end  of  this  tube  is 
placed  a  conical  tube  C,  the  lower  end  of  which  has  several 
notches  cut  in  it,  so  that  the  liquid  can  pass  under  when  placed 
as  shown  in  the  drawing.  The  lower  extremity  of  the  vessel 
A  is  ground  to  fit  into  the  mouth  of  the  receiver  B. 

The  above  apparatus  was  mentioned  by  Procter,  in  1849,  in 
his  article  on  "the  preparation  of  the  oleoresinous  ethereal  ex- 
tracts. ' ' 

1849 


Mohr,  Eedwood  and  Procter's  Pharmacy,  p.  272. 

A  is  an  ordinary  tin  displacer,  except  that  the  rim  c  is  soldered 
around  the  mouth,  in  such  a  manner  as  to  form  a  water  joint 
when  the  rim  of  the  cover  d  is  placed  in  it;  a  is  a  perforated 
diaphragm,  e  a  tin  tube  open  below  and  above.  The  latter  is 
soldered  to  the  lower  diaphragm,  through  which  it  passes,  while 
the  upper  diaphragm  slips  over  it  loosely.     In  using  the  dis- 


36  I^U  MEZ— THE  GALENICAL  OLEORESINS 

placer,  the  ingredients  are  introduced  around  the  tube  to  a 
suitable  height,  the  upper  diaphragm  put  in  its  place,  and 
menstruum  poured  on,  the  joint  half  filled  with  water  and  the  lid 
inserted.  The  atmosphere  of  the  bottle  B  communicates  with 
that  of  A  through  the  tube  e. 


This  form  of  percolator  was  mentioned  by  Procter  (1849)  in. 
his  article  on  "The  oleoresinous  ethereal  extracts." 


1849 


Mohr,  Eedwood  and  Procter's  Pharnmcy,  p.  270. 


Figure  A  is  a  glass  adapter,  which  is  selected  of  suitable  size. 
The  lower  extremity  of  this  is  partially  stopped  with  a  cork  cut 
as  represented  in  F.  A  layer  of  coarsely  pounded  glass  is  put 
over  the  cork,  and  above  this  a  layer  of  clean  sand,  thus  form- 
ing a  strainer  for  arresting  the  passage  of  the  solid  particles  of 
material  to  be  acted  upon.  The  end  of  the  adapter  is  fitted, 
by  means  of  a  perforated  cork,  into  the  mouth  of  the  bottle.  A 
glass  tube,  one  end  of  which  is  drawn  to  a  capillary  opening, 
is  also  fixed  in  the  cork  as  shown  at  C  so  as  to  allow  the  air  to 
escape  out  of  the  bottle  as  the  liquid  drops  in.  A  piece  of  blad- 
der may  be  tied  over  the  mouth  of  the  vessel  at  A  to  prevent 
the  evaporation  of  the  solvent,  but  a  few  pin  holes  must  be  made 
in  the  bladder  to  admit  of  the  ingress  of  air  as  the  liquid  passes 
into  the  receiver  below. 


APPARATUS  EMPLOYED 


37 


The  above  form  of  percolator  was  mentioned  by  Procter 
(1849)  in  his  article  entitled  The  Preparation  of  the  Oleoresin- 
ous  Ethereal  Extracts. 


1873 

Utensilien  zur  Bereitung  der  aetherischen  nnd  weingeistig- 
aetherischen  Extracte. 

Hager's  Commentar  zur  Pharmakopoea  Germanica,  1,  p.   620. 

This  consists  of  a  cylinder  hh  fitted  into  a  cork  /  which  is  in- 
serted into  the  neck  of  a  flask  or  bottle  g,  aa  is  a  cover  which 
serves  as  a  condenser.  In  the  lower  end  of  the  cylinder  &&  is 
a  tin  sieve  plate  ss  in  the  center  of  which  is  a  tin  tube  rr  en- 
closed in  a  glass  tube  vv.  The  glass  tube  is  held  firmly  in  place 
by  a  cork  at  each  end  pp.  The  condenser  aa  has  a  conical 
shaped  bottom  N  around  the  interior  of  which  run  two  cor- 
rugated rings  zz  of  tin.  The  space  a,  Fig.  B,  contains  cold 
water  which  enters  from  the  openings  cc  and  flows  out  through 


38 


DU  MEZ— THE  GALENICAL  OLEORESINS 


the  tubes  ee.  As  soon  as  the  menstruum  drops  through  color- 
less, the  top  aa  is  taken  off  and  D  put  on  in  its  place.  It  is 
also  a  condenser.  The  water  flows  in  at  a  and  off  through  &. 
The  conical  bottom  K  is  so  arranged  that  the  condensed  solvent 


drops  from  off  the  receiver  i  and  is  carried  off  into  a  flask 
through  the  outlet  e.  The  space  between  vv  and  aa  is  filled 
with  either  hot  or  cold  water. 


1873 

Utensilien  zur  Bereitung  der  aetherischen  und  weingeistig- 

aetherischen  Extracte. 

Hagers  Commentar  zur  Pharmakopoea  Germanica,  1,  p.  622. 

A  displacement  tube  D  with  a  wide  mouth  at  its  upper  end  is 
closed  with  a  cork  through  which  runs  a  thistle  tube  T.  The 
lower  end  is  pushed  through  a  cork  which  fits  tightly  in  a  re- 
ceiving bottle  R.  The  small  glass  tube  I  is  for  the  purpose 
of  letting  the  air  escape  from  the  receiver  R. 


APPARATUS  EMPLOYED 


^9 


1884 


Parish's  Treatise  on  Pharmacy,  p.  755 


A  percolator  of  tinned  copper  is  surrounded  by  a  jacket  of 
the  same  material ;  the  receiver  is  a  copper  vessel  with  two  necks 
into  one  of  which  the  percolator  is  secured,  the  other  is  connected 
with  a  pipe  leading  to  the  closed  head  of  the  percolator  which  is 
also  jacketed ;  on  the  other  side  of  the  head  is  a  perforated  plate 


40 


DU  MEZ— THE  GALENICAL  OLEORESINS 


of  tinned  copper,  which  distribute^  the  ether  over  the  surface  of 
the  drug  when  it  has  been  volatilized  by  placing  the  receiver 
in  hot  water.  After  the  exhaustion  of  the  drug,  the  receiver  is 
removed,  the  lower  orifice  of  the  percolator  closed,  and  the  head 
well  refrigerated;  a  stream  of  hot  water  is  then  passed  into  the 
jacket  around  the  percolator,  by  which  means  the  contained 
ether  may  be  recovered. 


1886 


Kemington's  Practice  of  Pharmacy  1886,  p.  366. 


The  apparatus  consists  of  a  cylindrical  percolator  fitted  into 
the  mouth  of  a  receiving  bottle  with  the  aid  of  a  cork.  The 
upper  part  of  the  percolator  being  closed  and  a  small  opening 
left  in  the  cork  to  allow  the  escape  of  air  from  the  receiving 
bottle. 


A  continuous  extraction  apparatus  can  be  made  of  this  per- 
colator by  enclosing  the  upper  part  in  a  suitable  case  and  pass- 
ing cold  water  between,  arranging  the  apparatus  like  a  Liebig's 
condenser.  A  glass  tube  is  connected  with  the  top  of  the  perco- 
lator and  the  mouth  of  the  bottle  by  rubber  tube  connections, 


APPARATUS  EMPLOYED 


41 


and  if  the  receiving  bottle  be  placed  in  a  water  bath  and  the  water 
gently  heated,  the  ether  will  evaporate  from  the  percolate,  the 
vapors  rising  in  the  tube  and  condensing  in  the  upper  part  of 
the  percolator. 


Lewin  R. 

Ein  neuer  Extractions  Apparat, 

Arch,  der  Pharm.,  215,  p.  74.     [Proc.  A.  Ph.,  35,  p.  12.] 


1887 


This  apparatus  is  adapted  for  1)  continuous  extraction  with 
hot  menstrua,  2)  continuous  extraction  with  cooled  menstrua, 
3)  recovery  of  the  menstrua  from  the  finished  extract  by  direct 
distillation. 

It  is  composed  of  three  easily  separable  principle  parts:  C, 
the  tinned  copper  still,  B,  the  copper  percolator,  which  is  pro- 
vided with  three  movable  sieve  bottoms  for  the  reception  of 

1)  For  continuous  extraction  with  hot  solvents,  the  vapors 
pass  from  the  still  C,  in  the  tube  1,  and  enter  through  the  tri- 


42  DU  MEZ— THE  GALENICAL  OLEORESINS 

faucet  I,  when  in  position  a,  through  tube  4,  into  the  percolator, 
the  substance  to  be  extracted.  A  is  the  condenser. 
B,  penetrate  the  substance  to  be  extracted,  and  condense.  The 
percolate  passes  into  the  receiver  and  from  this  flows  through 
the  tri-faucet  III  in  its  position  a,  through  the  tube  7,  again 
into  the  still,  to  repeat  this  course  as  long  as  it  may  be  desir- 
able. To  prevent  pressure  in  the  apparatus,  the  tube  2,  is 
removed  during  this  operation,  and  the  tri-faucet  II  is  placed 
in  position  a.  This  admits  the  vapor  into  the  cooling  worm,  A, 
which  thus  forms  a  safety  valve. 

2)  For  the  continuous  extraction  with  cooled  solvents,  the 
vapors  pass  from  the  still  C,  into  tube  1,  and  enter  through  the 
tri-faucet  I,  in  its  position  h,  through  tube  2,  into  the  cooling 
worm  A,  from  this  as  a  liquid  through  the  tri-faucet  II,  in  its 
position  a,  into  the  percolator,  and  so  through  the  substance  to 
be  extracted  into  the  still  as  before. 

3)  For  the  recovery  of  the  solvent  from  the  extract  by  direct 
distillation,  the  vapors  pass  from  the  still  C,  through  tube  1, 
through  the  tri-faucet  I,  in  its  position  h,  through  tube  2,  into 
the  cooler,  A,  through  the  tri-faucet  II  in  its  position  h,  into  the 
exit  tube  3,  which  latter  may  be  lengthened  at  pleasure. 

Portions  of  the  percolator  may  be  removed  from  the  receiver 
at  pleasure  through  the  tri-faucet  III,  in  its  position  c,  by  the 
tubes  2  and  3.  All  of  the  tubes  are  connected  or  disconnected 
by  good  screw  joints. 

Flueckiger,  F.  A.  1889 

Ein  zweckmaessiger  Extraktionsapparat. 
Arch.  d.  Pharm.,  227,  p.  162.     [Proc.  Am.  Pharm.  Assoc,  37, 
p.  338]. 

The  extraction  tube  A  is  provided  at  C  with  a  diaphragm 
from  the  center  of  which  a  small  tube  or  neck  extends  into  the 
funnel  D.  The  tube  B  F  attached  to  the  side,  passes  into 
a  tubulure  G,  which  is  provided  with  an  ordinary  cork  K 
by  means  of  which  communication  through  the  tube  B  F, 
between  the  upper,  and  the  lower  portions  of  the  apparatus 
may  be  cut  off  or  established.  Thus  causing  the  condensed 
liquid  to  return  through  the  drug  when  the  communication  is 
closed  or  allowing  the  liquid  to  be  distilled  off  when  it  is  open. 


APPARATUS  EMPLOYED 


43 


Caspar!  in  his  Treatise  on  Pharmacy  (1916)  describes  the  use 
of  this  apparatus  in  connection  with  the  preparation  of  the  oleo- 


resms. 


1890 

Szombazi  Soxhlet's  Extraction  Apparatus. 

Dingier 's  pol.  Journ.,  256,  p.  461.  [Zeitschrift  f  Anal.  Chem., 

19,  p.  365.] 


Maish  (1900)  first  suggested  the  use  of  this  apparatus  in  the 
preparation  of  the  oleoresins. 


44 


DU  MEZ — THE  GALENICAL  OLEORESINS 


Alpers,  William  C.  1896 

Oleoresinae. 
Merck's  Rep.,  5,  p.  593.   [Proc.  Am.  Pharm.  Assoc,  45,  p.  435.] 


The  apparatus  consists  of  a  cylindrical  percolator  a.  The 
upper  end  of  the  percolator  is  closed  with  a  large  cork  b  through 
which  two  holes  have  been  bored — the  one  for  receiving  a  bent 
glass  tube  c,  the  other  for  a  small  glass  funnel  d.  The  lower 
narrow  end  of  the  percolator  is  closed  by  a  cork  e  through  which 
a  straight  connecting  glass  cock  /  passes  into  another  perforated 
cork  g  that  closes  the  receiving  bottle  h.  This  cork  contains 
a  second  perforation  with  a  small  bent  glass  tube  i.  The  glass 
tubes  0  and  i  are  joined  by  means  of  a  small  piece  of  rubber 
tubing  at  k. 


1902 


Coblentz's  Handbook  of  Phannacy,  p.  290. 


(^ 


B 


A  is  a  percolator  with  a  stop  cock  C.     It  is  inserted  into  a 
receiver  B.     The  receiver  B  and  percolator  A  are  connected 


APPARATUS  EMPLOYED 


45 


with  a  tube  as  shown  in  the  figure  for  the  purpose  of  equalizing 
the  pressure  as  the  apparatus  is  closed  throughout. 


1908 


Brandel  and  Kremers,  Percolation,  p.  52. 


A  is  an  ordinary  conical  percolator  of  such  a  size  that  it  will 
not  be  more  than  two-thirds  filled  with  the  drug  to  be  extracted. 
B  is  a  round-bottom  flask,  containing  a  twice  perforated  stop- 
per, through  one  hole  of  which  a  glass  tube  connects  the  flask 
to  the  percolator.  Through  the  second  hole  is  inserted  the 
glass  tube  C  which  also  passes  through  the  cork  stopper  in  the 
top  of  the  percolator.  The  end  of  the  condenser  D  is  also  in- 
serted through  this  cork.  All  cork  connections  should  be  tightly 
sealed  with  gelatine. 

The  above  is  the  form  of  apparatus  which  was  used  in  the 
laboratory  in  the  preparation  of  the  oleoresins  when  500  grams 
or  more  of  the  drug  were  extracted. 


46  DU  MEZ— THE  GALENICAL  OLEORESINS 


Yield 

The  yield  of  oleoresin  is  a  variable  quantity  depending,  first 
of  all,  upon  the  oleoresin  content  of  the  particular  drug  from 
which  it  is  prepared.       Thus,  the  oleoresin  content  of  ginger 
is  only  about  one-half  that  of  the  aspidium  and  one-fourth  that 
of  cubeb.     Not,  only,  however,  does  the  oleoresin  content  vary 
with  the  different  drugs,  but  the  drug,  when  of  the  same  genus 
and   species,  may  show  a  variation   due  to  a  number  of  in- 
fluences, such  as  the  climate  in  which  grown,  time  of  harvest- 
ing, conditions  under  which  stored,  et  cetera.     As  an  illustra- 
tion of  these  influences,  aspidium  may  be  taken.       The  maxi- 
tnum  yield  of  oleoresin,  in  this  case,  is  obtained  from  the  freshly 
^dried  Russian  rhizomes  collected  in  the  month  of  September.^) 
^Or,  the  case  of  ginger  may  be  cited.       In  this  instance,  the 
African    rhizomes    harvested    at    maturity    (usually    in    Feb- 
:ruary)^)  give  the  largest  amount  of  oleoresin.     This  character- 
istic will  be  taken  up  in   detail  under  the  treatment  of  the 
'^individual  oleoresins.       The  other  important  factors  in  deter- 
mining the  amount  of  oleoresin  obtained,  in  general,  are  two 
in  number,  viz:  the  solvent  employed  in  extracting  the  drug, 
and  the  method  employed  in  operating  with  the  same.     Both 
of  these  factors  have  been  dealt  with  in  a  general  way  under 
the  two  preceding  headings.     They  will  also  be  discussed  more 
fully  in  connection  with  the  individual  preparations. 

Chemistry 

The  Chemistry  of  the  oleoresins  per  se  has  apparently  re- 
ceived but  little  attention,  except  in  the  case  of  the 
oleoresin  of  aspidium.  The  latter  has  been  the  subject 
of  numerous  investigations  and  its  chemistry  is  now  under- 
stood fairly  well.  Some  work  has  also  been  done  toward  de- 
termining the  composition  of  the  oleoresins  of  cubeb  and 
lupulin,  but  our  present  knowledge  of  the  chemistry  of  these 
preparations  is  still  very  indefinite. 

A  very  considerable  amount  of  work  has  been  done  toward 
clearing  up  the  chemistry  of  the  drugs  from  which  the  oleo- 
resins are  prepared,  and  it  is  from  this  source  that  we  are 


1  See    tables    of   yield    under   the   oleoresins    of    aspidium    and    ginger,    re- 
spectively. 


PHYSICAL  PROPERTIES  47 

obliged  to  obtain  what  information  we  have  concerning  the 
composition  of  most  of  these  preparations.  It  is  for  this  rea- 
son that  the  chemistry  of  the  drugs  from  which  the  oleoresins 
are  prepared  is  given  consideration  in  this  monograph.  See 
^'Chemistry  of  the  drug  and  its  oleoresin"  under  the  treatment 
of  each  individual  oleoresin. 

Physical  and  Chemical  Properties 

The  determination  of  the  physical  and  chemical  properties 
of  the  galenical  oleoresins  in  general  does  not  appear  to  have 
been  undertaken  systematically  in  the  past.  While  there  are 
numerous  references  in  the  literature  concerning  color,  odor, 
taste  and  consistence,  there  is  no  mention,  except  in  connection 
with  the  oleoresins  of*  aspidium  and  cubeb,  of  the  properties 
which  we  should  naturally  expect  to  find  under  a  description 
of  a  class  of  preparations  of  this  nature,  viz:  specific  gravity, 
refractive  index,  acid  number,  saponification  value,  et  cetera. 
This  condition  is  surprising  in  view  of  the  work  which  has 
been  done  along  this  line  in  connection  with  the  natural  pro- 
ducts of  the  same  name.  That  cognizance  is,  however,  being 
taken  of  the  subject  at  the  present  time  is  evidenced  in  the 
comparatively  recent  work  which  has  been  done  abroad  on  the 
oleoresin  of  aspidium.  In  the  latter  case,  the  methods  usually 
employed  in  fixing  the  standards  of  similar  natural  products 
were  applied,  and  with  considerable  success.  A  brief  general  dis- 
cussion of  these  properties  as  well  as  other  characteristics,  which 
have  been  mentioned  in  this  connection,  follows. 

Physical  Properties 
Color: 

The  color  is  a  characteristic  property  of  the  individual  mem- 
bers of  this  class  of  preparations.  Considered  with  respect 
to  a  single  member,  it  serves  in  some  cases  as  a  measure  whereby 
the  quality  of  the  product  may  be  roughly  determined.  Thus, 
a  brown  color  in  the  oleoresin  of  aspidium  indicates  an  inferior 
preparation,  in  the  making  of  which  old  deteriorated  rhizomes 
have  been  used,  whereas,  a  deep  green  color  is  said  to  indicate 
adulteration  with  salts  of  copper.  Likewise,  a  brown  color 
in  the  oleoresin  of  cubeb  warrants  the  opinion  that  ripe  in- 
stead of  unripe  fruits  have  entered  into  its  preparation.     How- 


48  DU  MEZ — THE  GALENICAL  OLEORESINS 

ever,  as  the  color  of  the  individual  preparations,  when  properly 
made,  varies  to  a  considerable  extent,  and  as  the  description  of 
exact  shades  is  a  difficult  matter,  this  property  as  described  in 
the  literature  is  naturally  somewhat  indefinite.  This  subject 
will  receive  further  consideration  of  the  treatment  of  the  in- 
dividual oleoresins. 

Odor: 

The  oleoresins  without  exception  possess  distinct  odors  re- 
sembling in  an  intensified  degree  those  of  the  drugs  from  which 
they  are  prepared.  In  general,  this  property  offers  a  ready 
means  of  identifying  these  preparations.  In  specific  instances,, 
it  may  also  serve  as  an  indication  of  the  quality  of  the  product. 
For  example,  a  rancid  odor  in  the  case  of  the  oleoresin  of  as- 
pidium  is  evidence  of  the  use  of  old  deteriorated  rhizomes  in 
its  preparation  or  of  undue  exposure  to  the  air  while  kept  in 
storage.  For  similar  reasons,  the  oleoresin  of  lupulin  may 
have  a  disagreeable  cheesy  odor.  Furthermore,  unevaporated 
solvent,  even  when  present  in  comparatively  small  amounts, 
may  be  most  easily  detected  by  this  means.  This  property  will  be 
discussed  in  greater  detail  under  the  individual  oleoresins. 

Taste: 

The  taste  of  the  individual  oleoresins,  like  the  odor,  is  a 
property  acquired  in  an  intensified  degree  from  the  drugs  from 
which  they  are  prepared.  Likewise,  this  property  also  serves 
as  an  acid  in  the  identification  of  these  preparations.  In  addi- 
tion, however,  it  has  been  made  the  basis  of  a  quantitative 
physiological  test  (^)  for  the  determination  of  the  quality  of 
the  oleoresins  of  capsicum  and  ginger.  For  a  further  discus- 
sion of  this  property,  see  the  individual  oleoresins. 

Consistence : 

The  U.  S.  P.  oleoresins,  with  the  exception  of  the  one  pre- 
pared from  lupulin,  are  liquids.  The  degree  of  fluidity,  how- 
ever, varies  with  the  individual  under  consideration,  with  the 
temperature  and  with  certain  other  conditions,  which  will  be  dis- 
cussed in  detail  under  the  separate  treatment  of  each  indi- 
vidual. The  oleoresin  of  lupulin  is  usually  of  the  consistence 
of  a  very  soft  extract. 


*  See  under  the  oleoresins  of  capsicum  and  ginger  respectively. 


PHYSICAL  PROPERTIES 


49 


SoluhUity: 

The  solubility  of  the  different  oleoresins  naturally  depends 
to  a  large  extent  on  the  solvent  which  was  employed  in  their 
preparation.  It  does  not,  however,  follow  from  this  statement 
that,  because  an  oleoresin  was  prepared  with  ether,  it  will  al- 
ways be  completely  soluble  in  the  same.  Some  of  these  prep- 
arations on  standing  undergo  chemical  changes  with  a  result- 
ing change  in  solubility.  For  example,  the  oleoresin  of  aspi- 
dium  forms  a  deposit  on  ageing,  and  the  deposited  material  is 
practically  insoluble  in  ether.  As  a  rule,  the  oleoresins,  when 
prepared  with  ether,  form  clear  or  slightly  cloudy  solutions 
with  absolute  alcohol,  acetone  and  chloroform,  whereas,  they 
are  only  partially  soluble  in  petroleum  ether  and  carbon  tetra- 
chloride. 

In  the  case  of  certain  members  of  this  class  of  preparations, 
this  property  has  been  of  considerable  value  in  detecting  adul- 
terations or  in  the  identification  of  the  solvent  which  was  em- 
ployed in  their  manufacture.  For  specific  instances  of  the 
application  in  this  connection,  see  under  the  oleoresins  of  aspi- 
dium  and  ginger. 

Specific  gravity: 

The  value  of  determining  the  specific  gravity  as  an  aid  to 
standardizing  the  oleoresins  appears  to  have  been  first  noted  by 
Procter.  In  1866,  he  published  data  showing  how  this  constant, 
in  the  case  of  the  oleoresin  of  cubeb,  varied  with  the  solvent 
employed  in  its  preparation,  and  further  pointed  out  that  a  low 
specific  gravity  observed  in  the  commercial  product  was,  in  one 
instance  at  least,  an  indication  of  the  incomplete  removal  of 
the  solvent,  ether.     Procter 's  observations  were  as  follows : 


Table  7.  —  The  specific  gravity  of  the  oleoresin  of  cubeb. 


Drug 

Solvent 

Specific  gravity 

Remarks 

Cubeb 

Alcohol 

Ether  

Benzin  

Ether 

at  76°  P. 
0,9850 
0.9675 
0.9325 
0.9000 

Prepared  by  Procter. 

Commercial  sample  containing  ether» 

This  work,  however,  appears  to  have  received  but  little  atten- 
tion as  there  is  no  further  mention  of  the  determination  of  this 


.50  DU  MEZ— THE  GALENICAL  OLEORESINS 

constant  in  this  connection  in  the  literature  until  1903.  In  that 
year,  the  English  firm  of  Southall  Brothers  and  Barclay  pub- 
lished a  statement  in  their  Laboratory  Reports,  in  which  a  stan- 
dard range  for  the  specific  gravity  of  the  oleoresin  of  aspidium 
was  given.  Interest  in  the  matter  again  seems  to  have  waned 
and  it  was  not  until  1911,  when  Parry  showed  that  the  last 
named  preparation  was  being  extensively  adulterated  with  castor 
oil,  that  the  necessity  for  standardizing  this  preparation  be- 
came apparent.  The  subject  was  then  taken  up  in  earnest, 
however,  and  in  1913,  no  less  than  four  articles  on  the  deter- 
mination of  the  physical  and  chemical  constants  of  the  oleo- 
resin of  aspidium  made  their  appearance.  In  each  of  these, 
the  determination  of  the  specific  gravity  was  given  some  con- 
sideration. 

From  the  foregoing  brief  resume  of  the  literature  on  this  sub- 
ject, it  becomes  apparent  that  the  determination  of  the  ^ecific 
gravity  as  a  factor  in  evaluating  the  oleoresins  has  received 
consideration  in  connection  with  but  two  of  the  official  prepara- 
tions. Furthermore,  that  practical  use  has  been  made  of  this 
constant  only  in  the  case  of  the  oleoresin  of  aspidium.  The 
results  obtained  with  respect  to  these  two  preparations,  how- 
ever, are  deemed  to  be  of  sufficient  importance  to  warrant  the 
determination  of  this  constant  in  the  case  of  the  other  members 
of  this  class  of  preparations. 

The  manner  in  which  this  constant  was  determined  by  the 
above  mentioned  investigators  does  not  become  apparent  from 
their  work  as  reported  in  the  literature.  It  is  thought,  how- 
ever, that  an  ordinary  glass  pycnometer  and  chemical  balance 
were  employed  for  this  purpose.  In  the  determinations  made 
in  the  laboratory,  a  10  cubic  centimeter  pycnometer  was  used, 
except  in  the  case  of  the  oleoresin  of  lupulin  which  was  usually 
too  thick  to  handle  in  this  manner.  For  the  determination  of 
the  specific  gravity  of  the  latter,  a  Nicholson's  hydrometer  was 
employed.     All  determinations  were  made  at  25°  C. 

The  results  as  obtained  in  the  laboratory  and  those  reported 
elsewhere  will  be  discussed  in  detail  under  the  treatment  of  the 
individual  oleoresins. 

Refractive  index: 

The  determination  of  the  refractive  index  has  received  con- 
sideration only  in  connection  with  the  standardization  of  the 


CHEMICAL.  PROPERTIES  5J 

oleoresin  of  aspidium.  In  this  case,  it  has  proven  to  be  of  par- 
ticular value  in  detecting  adulteration  with  castor  oil  as  was 
first  pointed  out  by  Parry  in  1911.  Subsequent  work  by  other 
investigators  has  not  only  confirmed  Parry's  observations,  but 
has  shown  that  in  some  instances  a  low  refractive  index  may  be 
an  indication  of  a  low  filicin  content  due  to  natural  causes^) 
as  well. 

Since  most  of  the  other  official  oleoresins  are  sufficiently  trans- 
parent to  permit  of  the  direct  determination  of  this  constant, 
it  was  thought  that  such  determination  might  likewise  prove  to 
be  of  some  aid  in  standardizing  these  preparations.  That  such 
an  opinion  has  proven  to  be  correct  will  be  shown  in  connection 
with  the  discussion  of  this  topic  under  the  individual  cases. 

For  the  determination  of  this  constant  in  the  laboratory,  the 
Abbe  refractometer  was  employed,  all  observations  being  made 
at  25°  C.  In  those  cases  (the  oleoresins  of  ginger  and  lupulin) 
where  the  color  was  too  intense  to  permit  of  a  direct  determina- 
tion being  made,  the  oleoresin  was  dissolved  in  an  equal  volume 
of  castor  oil  and  the  refractive  index  computed  from  the  follow- 
ing formula : 

njj  (b)  ==  2nj^^  (a  +  b)  —  n^  (a) 

a  =  refractive  index  of  castor  oil. 
b=         ''  ''      ''   oleoresin. 

Chemical  Properties 
Loss  on  Hearting  : 

The  oleoresins  without  exception  lose  weight  on  drying.  This 
loss  is  usually  referred  to  in  the  literature  as  the  moisture  con- 
tent. It  has  been  determined  by  heating  the  preparation  at 
100  to  105°  C.  for  a  definite  period  of  time,  or  until  of  con- 
stant weight.  The  fallacy  of  designating  the  loss  of  weight 
thus  obtained  as  the  moisture  content  becomes  evident  when  we 
take  into  consideration  the  fact  that  these  preparations  con- 
tain volatile  substances  other  than  water,  which  would  also  be 
removed  by  heating  to  a  temperature  of  100°  C.     Indeed,  the  oily 


^  The  male  fern  rhizomes  have  been  shown  to  vary  in  fllicin  content  due 
to  the  climatic  conditions  under  which  they  were  grown,  time  of  harvesting, 
€t  cetera.     See  under  "Drug  used,  its  collection,  preservation,  etc." 


52  DU  MEZ— THE  GALENICAL  OLEORESINS 

nature  of  these  preparations  exclude  the  presence  of  any  great 
quantity  of  moisture.  This  statement  has  been  borne  out  by 
laboratory  experiments.  Attempts  to  determine  the  moisture 
by  means  of  the  xylene^)  method  failed  to  reveal  the  presence 
of  a  measurable  amount  of  water  in  any  of  the  samples  examined. 
The  loss  in  weight  is,  therefore,  due,  ordinarily,  to  the  removal 
of  volatile  oil  and  in  exceptional  cases  to  the  removal  of  un- 
evaporated  solvent.  Such  being  the  case,  the  determination  of 
this  constant  serves  as  a  means  of  measuring  the  amount  of 
volatile  oil  naturally  occurring  in  these  preparations  and  as  a 
means  of  detecting  the  presence  of  unevaporated  solvent. 

The  amount  of  weight  lost  by  the  oleoresins  when  deter- 
mined as  stated  above  varies  greatly  with  the  individual 
members  comprising  this  class  of  preparations.  The  oleoresin 
of  cubeb  which  contains  a  comparatively  large  amount 
of  volatile  oil  naturally  sustains  a  comparatively  great 
loss,  while  the  oleoresin  of  capsicum  which  contains 
a  small  amount  of  volatile  matter  shows  but  a  slight  loss. 
There  is  noted  a  further  variation  in  the  case  of  each  individual 
due  to  a  variation  in  the  amount  of  volatile  matter  naturally 
occurring  in  the  drug  from  which  the  oleoresin  was  obtained, 
or  to  a  variation  in  the  conditions  under  which  the  individual 
was  prepared.  As  an  illustration,  the  oleoresin  of  cubeb  may 
be  cited.  The  volatile  oil  content  of  cubeb  is  stated  to  be  10  to 
18  per  cent.  A  much  greater  variation  is,  therefore,  to  be  ex- 
pected in  the  oleoresin  which  represents  only  the  alcohol  soluble 
portion  of  the  drug.  With  respect  to  the  conditions  under 
which  the  oleoresin  of  cubeb  is  prepared,  observations  in  the 
laboratory  have  shown  that  the  preparation  will  contain  a  larger 
amount  of  volatile  oil  when  the  solvent  is  allowed  to  evaporate 
spontaneously  at  room  temperature,  than  when  the  same  is  re- 
moved by  evaporation  on  a  water  bath.  In  most  cases,  the 
variation,  due  to  the  difference  in  solvent  used  in  extracting 
the  oleoresins,  appears  to  be  so  slight  as  to  be  almost  negligible. 
In  the  case  of  the  oleoresin  of  pepper,  however,  there  is  a  very  no- 
ticeable difference.  This  is  very  likely  due  to  the  nature  of  the 
preparation,  its  viscosity  making  it  difficult  to  remove  the  last 
traces  of  the  less  volatile  solvents  without  the  application  of 
heat. 


1  U.  S.  Dept.  Agric,  Forest  Service,  Circ.  134. 


CHEMICAL.  PROPERTIES  53 

In  the  determinations  of  this  nature  made  in  the  laboratory, 
a,  weighed  amount  of  the  oleoresin  (about  2  grams)  was  heated 
in  an  electric  oven  at  100°  C.  for  3  hours,  cooled  in  a  desiccator 
and  weighed,  the  difference  in  the  two  weights  being  taken  as 
the  loss. 

A  more  detailed  consideration  of  this  subject  will  be  found 
under  the  treatment  of  the  individual  oleoresins. 

Ash  Content: 

The  determination  of  the  ash  content  of  the  oleoresins  is 
of  special  value  in  identifying  the  solvents  which  have  been  used 
in  their  preparation.  Such  determinations,  made  in  this 
laboratory,  also  by  the  firm  of  Dieterich^)  in  Helfenberg,  have 
shown  that,  while  there  is  as  a  rule  comparatively  little  dif- 
ference in  the  ash  content  of  these  preparations,  when  prepared 
with  the  same  solvent,  there  is  a  marked  variation  in  the  case 
of  each  individual  when  different  solvents  are  employed.  The 
oleoresin  of  lupulin  is  an  exception  to  this  rule.  Its  ash  con- 
tent varies  to  a  considerable  extent  even  when  prepared  with 
the  same  solvent. 

In  addition  to  the  above,  the  qualitative  examination  of  the 
ash  of  commercial  samples  has  revealed  the  fact  that  nearly  all 
of  them  contain  copper,  due  in  most  cases  to  the  action  of  the 
free  fatty  acids  on  the  utensils  employed  in  their  preparation* 
In  some  instances,  the  presence  of  the  metal  must  be  attributed 
to  the  addition  of  copper  salts  for  the  purpose  of  imparting 
the  desired  green  color  to  preparations  of  inferior  quality.  See 
under  the  adulteration  of  the  oleoresins  of  aspidium  and  cubeb, 
respectively. 

The  ash  content  of  the  oleoresins  examined  in  the  laboratory 
was  determined  as  directed  by  the  last  edition  of  the  United 
States  Pharmacopoeia  under  ''Determination  of  Ash  or  Non- 
volatile Matter,'*  p.  589. 

Copper,  when  present,  was  identified  by  the  blue  color  of  the 
solution  formed  when  the  ash  was  dissolved  in  a  few  drops  of 
hydrochloric  acid,  diluted  with  water,  and  ammonium  hy- 
droxide solution  added. 


^  The  firm  of  Dieterich  has  for  a  number  of  years  determined  the  ash 
content  of  the  oleoresins  of  aspidium  and  cubeb.  A  tabulation  of  the  re- 
sults as  obtained  by  this  firm  will  be  found  under  the  separate  treatment 
of  these  oleoresins. 


54  I^U  MEZ— THE  GALENICAL  OLEORESINS 

For  a  more  detailed  discussion  of  this  subject,  see  under  in- 
dividual oleoresins. 

Acid  Number: 

Kremel  in  1887  determined  the  acid  numbers  of  the  oleo- 
resins of  aspidium  and  cubeb.  Inasmuch,  however,  as  he  made- 
but  one  determination  in  each  case,  no  conclusions  can  be  drawn 
from  his  work.  Similar  determinations  made  in  this  laboratory 
on  all  of  the  official  oleoresins  show  that  this  property  varies, 
greatly  depending  on  the  particular  individual  under  considera- 
tion. Furthermore,  that  no  general  statement  can  be  made  aa 
to  -its  value  in  fixing  the  standards  of  these  preparations,  but 
that  it  is  of  importance  when  considered  in  connection  with 
individual  cases  as  will  be  brought  out  later. 

For  the  manner  in  which  this  constant  was  determined  in 
the  laboratory,  see  the  United  States  Pharmdcopoeia,  ninth  re- 
vision, (1916),  p.  591. 

Saponification  Value  : 

The  saponification  values  of  the  official  oleoresins,  as  deter- 
mined in  this  laboratory  and  elsewhere,^)  indicate  that  this 
property  may  be  an  important  factor  in  fixing  standards  for 
these  preparations.  The  results  obtained  by  Parry,  Harrison 
;and  Self,  and  others  show  that  in  the  case  of  the  oleoresin  of 
aspidium,  the  saponification  value  varies  directly  as  the  filicin 
content,  and  is,  therefore,  useful  as  a  check  on  the  determina- 
tion of  the  latter.  Considered  in  connection  with  such  of  these 
preparations  as  contain  easily  oxidizable  substances,  an  abnor- 
mally high  saponification  value  is  very  likely  caused  by  an  in- 
crease in  the  acid  content  due  to  the  action  of  the  oxygen  of  the 
air,  and  is  thus  an  indication  of  an  old  product^)  or  of  improper 
care  in  storing.  As  an  example,  the  oleoresin  of  lupulin  may 
be  cited.  In  this  case,  a  high  saponification  value  signifies  an 
old  preparation  or  one  that  has  been  prepared  from  deteriorated 
drug.^)  These  factors,  together  with  the  influence  of  the  solvent 
employed  and  the  method  of  preparation  on  this  property,  will 


*  Saponification  values  have  only  been  determined  in  the  past  in  the  case 
of  the  oleoresin  of  aspidium  and  in  one  instance  in  the  case  of  the  oleoresin 
of  cubeb. 

2  See  oleoresin  of  aspidium. 

2  See  oleoresin  of  lupulin. 


SPECIAL  TESTS  55. 

be  considered  in  greater  detail  under  the  treatment  of  the  in- 
dividual members. 

The  manner  in  which  this  constant  was  determined  in  the 
laboratory  is  described  on  p.  590  of  the  United  States  Phar- 
macopma,  ninth  revision. 

Iodine  value: 

The  determination  of  the  iodine  value  as  an  aid  to  the 
standardization  of  the  oleoresins  appears  to  have  been  first  em- 
ployed by  the  firm  of  Dieterich  in  Helfenberg  in  1904,  however^ 
only  in  the  case  of  the  oleoresin  of  aspidium.  It  has  since  re- 
ceived further  practical  application,  in  connection  with  the  same 
preparation,  by  the  English  firm  of  Evans  Sons,  Lescher  and 
Webb,  while  a  number  of  similar  determinations  have  been  made 
by  the  author.  The  results^)  obtained  with  respect  to  this 
preparation  show  that  the  iodine  value  varies  directly  as  the 
filicin  content,  and,  therefore,  serves  as  another  check  on  the 
determination  of  the  latter  constituent. 

With  respect  to  the  other  official  oleoresins,  it  may  be  stated 
that,  as  a  general  rule,  the  iodine  value  is  high  in  the  case  of 
those  preparations  which  contain  a  large  amount  of  unsaturated 
constituents  of  ether  fatty  or  volatile  oil.^)  Further  than  this,, 
it  may  be  influenced  largely  by  the  nature  of  the  other  consti- 
tuents of  these  preparations  and  will  be  considered  in  detail  in 
connection  with  the  treatment  of  each  individual. 

For  the  method  employed  in  the  laboratory  in  the  determina- 
tion of  this  constant,  see  the  United  States  Pha/rnmcopwia,  ninth 
revision,  p.  590. 

Special  Tests 

While  the  different  official  oleoresins  can,  as  a  rule,  be  identi- 
fied without  difficulty,  the  use  of  various  adulterants  in  their 
preparation,  through  ignorance  in  some  cases,  or  with  willful 
intent  on  the  part  of  unscrupulous  manufacturers,  has  made 
it  necessary  to  guard  against  this  practice  by  making  use  of 
certain  qualitative  and  quantitative  tests.  As  will  be  brought 
out  later,  such  tests  have  been  applied  principally  to  the  pre- 
parations official  in  foreign  countries,  namely:  the  oleoresins 


*  See  under  oleoresin  of  aspidium. 
^  See  under  oleoresin  of  cubeb. 


56  DU  MEZ— THE  GALENICAL.  OLEORESINS 

of  aspidium  and  cubeb.  No  tests  of  this,  or,  as  a  matter  of  fact, 
of  any  kind  have  been  included  in  the  United  States  Phar- 
macopoeia.  It  is  thought,  however,  that  if  interest  in  these  prep- 
arations could  be  awakened  in  this  country,  the  need  of  sim- 
ilar precautions  with  respect  to  all  of  the  official  oleoresins  would 
become  apparent. 

Qualitative  Tests: 

Inasmuch  as  the  common  physical  properties,  such  as  odor, 
taste  and  appearance,  are  very  characteristic  of  the  oleoresins, 
it  is  hardly  necessary  to  resort  to  other  means  for  their  identi- 
fication. It  appears,  however,  that  the  use  of  the  so-called 
false  cubebs  in  the  preparation  of  the  oleoresin  of  cubeb  has 
made  necessary  a  more  certain  method  of  identification.  Such 
a  method,  based  on  the  red  color  produced  when  concentrated 
sulphuric  acid  is  added  to  the  oleoresin  prepared  from  the  gen- 
uine fruit,^)  has,  therefore,  been  given  in  most  of  the  late  Eur- 
opean pharmacopoeias.  Likewise,  the  use  of  other  species  of 
fern  in  the  preparation  of  the  oleoresin  of  aspidium  caused  a 
qualitative  test  for  this  preparation  to  be  included  in  the  late 
editions  of  the  Austrian,  Hungarian  and  Netherlands  phar- 
macopoeias. For  the  details  of  these  methods,  see  qualitative 
tests  under  the  respective  oleoresins. 

Quantitative  Tests: 

On  the  whole,  very  little  has  been  done  in  the  past  toward 
developing  quantitative  methods  for  the  evaluation  of  the  oleo- 
resins. This  condition  is  perhaps  due,  for  the  main  part,  to  an 
imperfect  knowledge  of  the  chemistry  of  most  of  these  prepara- 
tions, as  well  as  to  the  lack  of  exact  information  concerning  the 
constituents  of  therapeutic  value.  In  the  case  of  the  oleoresin 
of  aspidium,  however,  the  therapeutic  value  of  the  preparation 
has  been  shown  to  depend  upon  a  number  of  acid  constituents, 
the  quantity  present  varying  through  natural  and  artificial  causes. 
As  a  result,  various  methods^)  for  the  determination  of  the  total 
acid  content  have  been  devised  and  are  in  use  at  the  present 
time,  a  modification  of  the  original  method  of  Fromme  being 
officially  recognized  in  the  late  edition  of  the  British  and  Swiss 


^  Dekker  states   that   the   so-called  false   cubebs   give   a  yellow   color  with 
concentrated  sulphuric  acid.     Pharm.  Ztgr.   (1912),   84,  p.  845. 
2  See  under  oleoresin  of  aspidium. 


SPECIAL,  TESTS  57 

pharmacopoeias.  The  only  other  work  of  this  nature  appears 
to  have  been  done  quite  recently  (1914)  by  the  H.  K.  Mulford 
Co.  in  the  standardization  of  the  oleoresins  of  capsicum  and 
ginger.  This  firm  has  devised  a  physiological  method  for  this 
purpose  based  on  the  extreme  pungency  of  these  preparations, 
the  highest  dilutions  in  which  these  preparations  (on  the  aver- 
age) are  still  perceptable  to  the  taste  being  taken  as  standards. 

Experiments  conducted  in  the  laboratory  in  preparation  for 
this  monograph  have  shown,  not  only  that  there  is  an  oppor- 
tunity for  improving  on  some  of  the  above  mentioned  methods, 
but  that  there  is  need  for  the  development  of  quantitative  meth- 
ods which  may  be  applied  to  the  other  individuals  of  this  class 
as  well.  With  respect  to  the  forepart  of  this  statement,  it  Is 
thought  that  a  gravimetric  method  for  the  estimation  of  the 
pungent  priniciples  (gingerol)  in  ginger  would  be  an  improve- 
ment over  the  physiological  method  of  the  Mulford  Co.  as  per- 
sonal idiosyncrasy  would  thus  be  eliminated.  Trials  with  the 
method  of  Garnett  and  Grier^)  (for  the  estimation  of  gingerol 
in  ginger)  adapted  to  the  oleoresin  appear  to  indicate  the  cor- 
rectness of  this  opinion.  In  the  case  of  the  oleoresin  of  capsi- 
cum, however,  the  physiological  method  apparently  offers  the 
only  practical  course  at  the  present  time,  in  view  of  the  fact 
that  the  active  constituent,  capsaicin,  is  present  in  such  minute 
quantities  that  an  accurate  gravimetric  determination  would  be 
a  difficult  matter. 

In  considering  the  application  of  new  methods,  the  work  done 
in  this  laboratory  on  the  oleoresin  of  pepper  may  be  cited. 
Since  the  therapeutical  value  of  this  preparation  is  apparently 
due  to  its  piperine  content,  a  method  for  the  quantitative  de- 
termination of  this  constituent  appeared  to  be  desirable.  With 
this  object  in  view,  the  nitrogen  present  was  determined  by  the 
Kjeldahl  method  and  the  piperine  content  computed  therefrom. 
Some  very  interesting  results  were  obtained.^)  As  to  further 
possibilities  along  this  line  the  determination  of  the  apiol  con- 
tent of  the  oleoresin  of  parsley,  or  the  estimation  of  the  quantity 
of  total  acid  resins  present  in  the  oleoresin  of  cubeb  may  be- 
mentioned. 


*  See  under  oleoresin  of  ginger. 
2  See  under  oleoresin  of  pepper. 


53  DU  MEZ— THE  GALENICAL  OLEORESINS 


Adulterations 

The  examination  of  commercial  samples  of  the  oleoresins  has 
shown  that  they  are  all  adulterated  at  times.  With  respect  to 
most  of  these  preparations,  adulteration  is  thought  to  be  acci- 
dental, 6.  g.  the  presence  of  copper  in  nearly  all  samples  due  to 
the  use  of  copper  utensils  in  the  manufacture  of  the  same,  or 
the  use  of  ripe  instead  of  unripe  fruits  in  the  preparation  of 
the  oleoresin  of  cubeb.  In  some  cases,  however,  adulteration 
has  been  practiced  with  willful  intention  to  defraud,  as  for 
example,  the  addition  of  fatty  oils  to  the  oleoresins  of  aspidium 
and  cubeb.  Other  instances  of  this  kind  will  be  given  con- 
sideration under  the  treatment  of  the  individual  oleoresins. 


PART  II— INDIVIDUAL  OLEORESINS 
OLBORESIN  OP  ASPIDIUM 

Synonyms 

Aceite  de  Helecho  Macho,  Sp.  P.  1905. 

Aetheres  pafran-Kivonat,  Hung.  P.  1880. 

Aetherhaltiges  FarrenTcraut extract y  Aust.  P.  1844. 

Aetherisches  Farrnkrautextract,  Pruss.  P.  1830.  ; 

Aetherisches  Farrnkrautwurzel  Extract,  Bad.  P.  1841. 

AlvejuurieTcstrakti,  Finn.  P.  1914.  , 

Balsamo  de  Helecho,  Dorvault,  L'Officine,  Sp.  Trans.  1879. 

Balsamum  Filicis,  Pareira,  Mat.  Med.  1854. 

Baum^  de  Fougere,  Dorvault,  L'  Officme,  1898. 

Braegne-Extract,  Dan.  Mil.  P.  844. 

Bregnerod  Extract,  Nor.  P.  1870. 

Bregnerodelcstralct,  Nor.  P.  1895. 

BregnerotekstraM,  Nor.  P.  1913. 

Estratto  di  Felce  Maschio,  Swiss.  P.  1907. 

Estrato  di  Felce  Maschio  Etereo,  Ital.  P.  1902. 

Ethereal  Extract  of  Male  Fern,  Journals. 

Extract  of  Male  Fern,  Jap.  P.  1907. 

Extract  van  Mannetjes-Varen,  Nethl.  P.  1871.  ■  * 

Extracto  de  Feto  Macho,  Port.  P.  1876. 

Extracto  de  Feto  Macho  Ethereo,  Port.  P.  1876. 

Extracto  Etereo  Helecho,  Sp.  P.  1884. 

Extracto  Ethereo  de  Helecho  M<acho,  Sp.  P.  1905. 

Extracto  oleo-resinoso  de  Helecho,  Dorvault,  L'Officine,  Sp.  Trans.  1879. 

Extractu  de  Filice  Mascule,  Roum.  P.  1874. 

Extractu  di  Felce  Machio,  Swiss.  P.  1865. 

Extractum  Aethereum  Filicis,  Sp.  P.  1884. 

Extractum  Aethericum  Filicis,  Fr.  P.  1866. 

Extractum  Aethericum  Filicis  Maris,  Fr.  P.  1866. 

Extractum  Aspidii,  Nor.  P.  1854. 

Extractum  di  Felce  Machio  Etereo,  Port.  P.  1876. 

Extractum  Filicis,  G.  P.  1900. 

Extractum  Filicis  aethereum,  Pruss.  P.  1861. 

Extractum  Filicis  liquidum,  B.  P.  1914. 

Extractum  Filicis  Maris  aethereum,  Ital.  P.  1902. 

Extractum  Filicis  oleoso-resinosum,  Jourdan,  Univ.  P.  1832. 

Extractum  Badicis  Filicis  Maris  athereum.  Bad.  P.  1841. 


go  DU   MEZ— THE   GALENICAL   OLEORESINS 

Extractum  Stipitum  Aspidii,  Nor.  P.  1854. 

Extrait  de  Fougere,  Belg.  P.  1906. 

Extrait  de  Fougere  Male,  F.  P.  1908. 

Extrait  Ethcre  de  Fougere,  Belg.  P.  1854. 

Extrait  EtMre  de  Fougere  Male,  Fr.   P.   1866. 

Extrait  oleo-resineux  de  Fougere,  Bern.  P.  1852. 

Extrait  oleo-resineux  de  Fougere  Male,  Fr.  P.  1908. 

Farnextrakt,  Ger.  P.  1900. 

Farrenkr<iutextralct,  Bern.  P.  1852. 

Farrnwurzel  Extract,  Swiss.  P.  1865. 

Filicis  Extractum,  Belg.  P.  1906. 

Filixextrakt,  Journals. 

Huile  de  Fougere  Male,  Belg.  P.  1854. 

Huile  de  Fougere  de  Peschier,  Bern.  P.  1852. 

Liquid  Extract  of  Fern  Root,  Br.  P.  1864. 

Liquid  Extract  of  Male  Fern,  Br.  P.  1885. 

Oil  of  Filix  mas,  Parrish,  Treat,  on  Pharm.  1867. 

Oil  of  Male  Fern,  Journals. 

Oleoresin  of  Fern,  U.  S.  P.  1870. 

Oleoresin  of  Male  Fern,  U.  S.  P.  1910. 

Oleoresina  Aspidii,  U.  S.  P.  1910. 

Oleo-resina  de  Helecho,  Dorvault,  L'Officine,  Sp.  Trans.  1879. 

Oleoresina  Filicis,  U.  S.  P.  1860. 

Oleo-Besina  Filicis,  Peschier,  Ver.  P.  der  Lond.,  Edinb.,  and  Dub.  Med. 

Coll.  1827. 
OUo-r^sine  de  Fougere,  Dorvault,  L'Officine,  1898. 
Oleum  Filicis,  Hung.  P.  1861. 
Oleum  Filicis  Maris,  Sp.  P.  1905. 
Oleum  Filicis  Maris  aethereum,  Swiss.  P.  1865. 
Oleum  Filicis  Peschieri,  Pareira,  Mat.  Med.  1854. 
Oleum  Filicis  pingue  resinosum  Geiger's  P.  1835 
Oleum  Badicis  filicis,  Strump.  Allg.  P.  18661. 
Orbunksrot  Extrakt,  Swed.  P.  1901. 
Pafran-Kivonat,  Hung.  P.  1871. 
Varenextract,  Neth.  P.  1905. 
Wurmfarnextrakt,  Swiss.  P.  1893. 
Wurmfarnoel,  U.  S.  Disp.  1907. 


OL.EORESIN  OF  ASPIDIUM  Q\ 


History 


The  oleoresin  of  aspidium,  or  Huile  de  Fougere  Male  as  it 
was  originally  known,  was  first  prepared  by  Peschier  in  1825.^ 
The  advantages  of  Peschier 's  preparation  over  the  forms  in 
which  male  fern  was  being  administered  at  the  time  were  quickly 
noted  and  it  received  almost  immediate  recognition  throughout 
Europe.  The  rapidity  with  which  it  was  taken  up  by  the 
medical  profession  is  evidenced  in  the  fact  that  it  was  mentioned 
in  the  Vereinigte  Pharmacopoeen  der  Londoner,  Edingurgher 
und  Duhliner  Medicm<e  Collegien,  a  German  translation  of  the 
pharmacopoeias  of  London,  Edinburgh  and  Dublin,  which  ap- 
peared in  1827,  and,  that  two  years  later  (1829),  it  became  of- 
ficial in  the  Prussian  Pharmacopoeia.  Its  introduction  into 
other  European  pharmacopoeias  followed,  as  a  general  rule,  in 
the  chronological  order  of  their  appearance  or  revision,  whereas, 
it  was  the  last  of  this  class  of  preparations  to  be  admitted  to  the 
United  States  PhQrmacoposia  previous  to  the  ninth  revision, 
having  been  recognized  for  the  first  time  in  the  edition  of  1870. 
At  the  present  time,  it  is  the  only  preparation  of  this  kind 
which  is  official  in  all  of  the  national  pharmacopoeias.  How- 
ever, it  is  only  in  the  United  States  where  it  is  officially  recog- 
nized under  the  title  oleoresin,  it  being  classed  as  an  extract 
in  all  of  the  foreign  pharmacopoeias.  For  a  better  apprecia- 
tion of  this  fact,  see  the  preceding  table  of  synonyms. 

A  better  idea  of  the  popularity  of  this  preparation  and  the 
rate  at  which  it  came  into  prominence  will  be  obtained  from 
the  following  table  in  which  are  chronologically  enumerated  the 
names  of  the  pharmacopoeias  of  the  countries,  states  and  muni- 
cipalities where  it  first  received  official  recognition,  also,  the 
dates  of  appearance  of  the  succeeding  editions  in  which  it  occurs. 

Prussian  Pharmacopoeia  —  1829,  1846,  1862. 
Pharmacopoeia  of  Baden  —  1841. 
Austrian  Pharmacopoeia  — 1844,  1869,  1889,  1906. 
Pharmacopoeia  of  Schleswig-Holstein  —  1844. 


1  Gebhardt  in  1821,  and  Morin  in  1824,  in  their  analyses  of  male  fern, 
extracted  the  rhizomes  with  ether  and  obtained  what  they  termed  a  thick, 
green,  fatty  oil.  This  was,  of  course,  the  Huile  de  Fougere  of  Peschier. 
Neitlier  of  these  investiefators,  however,  pointed  out  its  value  as  a  galenical 
preparation,  although,  the  latter  stated  that  he  considered  it  to  be  the  ther- 
apeutically active  principle  of  the  rhizomes. 


g2  DU  MEZ— THE  GALENICAL  OLEORESINS 

Swedish  Pharmacopoeia— 1846,  1869,  1879,  1888,  1901,  1908. 
Pharmacopoeia  of  Berne  —  1852. 
Belgian  Pharmacopoeia — 1854,  1885,  1906. 
.     Norwegian  Pharmacopoeia  — 1854,  1870,  1879,  1895,  1913. 
Pharmacopoeia  of  Hannover — 1861. 

Pharmacopoeia  of  Hessia  —  1862.  \^    i 

British  Pharmacopoeia  — 1864,  1867,  1885,  1898,  1814. 
Swiss  Pharmacopoeia— 1865,  1872,  1893,  1907. 
French  Pharmacopoeia  — 1866,  1884,  1908. 
Austrian  Pharmacopoeia— 1869,  1889,  1906. 
Hungarian  Pharmacopoeia  — 1871,  1888,  1909. 
Netherlands  Pharmacopoeia  — 1871,  1889,  1909. 
German  Pharmacopoeia — 1873,  1882,  1890,  1900,  1910. 
United  States  Pharmacopoeia  — 1870,  1880,  1890,  1900,  1910. 
Eoumanian  Pharmacopoeia  — 1874. 
Portuguese  Pharmacopoeia  — 1876. 
Spanish  Pharmacopoeia  — 1884. 
Italian  Pharmacopoeia — 1892,  1902,  1909. 
Danish  Pharmacopoeia  —  1893,  1907. 
Japanese  Pharmacopoeia — 1907. 
Eussian  Pharmacopoeia — 1910. 
Finnish  Pharmacopoeia  — 1914. 


Drug  Used,  Its  Collection,  Preservation,  Etc. 

The  rhizomes  directed  by  all  of  the  present  day  pharma- 
copoeias to  be  used  in  the  preparation  of  the  oleoresin  of  as- 
pidium  are  those  of  the  male  fern^  now  referred  by  botanists. 
to  the  genus  Dryopteris  as  Dryopteris  Filix-mas  (Linne)  Schott. 
As  male  fern,  especially  in  the  older  works  on  pharmacy,  has  been 
referred  to  genera  other  than  Dryopteris,  the  following  table  of 
botanical  synonyms  is  given : 


^  The  rhizomes  of  ferns  other  than  those  which  have  been  offlcially  recog- 
nized are  said  to  yield  oleoresins  which  are  active  in  the  expulsion  of  the 
tapeworm. 

Kuersten  states  that  the  rhizomes  of  Aspidium  athamanticum  Kunse  yield 
a  preparation  which  is  as  active  as  that  obtained  from  male  fern.  Arch, 
d.  Pharm.  (1891),  229,  p.  258. 

Lauren  reports  the  use  of  an  extract  in  Finland  prepared  from  Aspidium- 
spinulosum  Sw.  which  he  states  is  very  active  as  a  teniafuge.  Finska 
Laegaresaellck.  Handl.    (1897),  p.   9;  Pharm.  Centralh,    (1897),  39,   p.   775. 

Rosendahl  suggests  that  the  rhizomes  of  Dropteris  dilata  replace  those 
of  Dryopteris  Filix-mas  in  the  preparation  of  the  oflflcial  oleoresin  as  he  has 
found  them  to  be  four  times  as  active  as  the  latter  in  the  expulsion  of 
Bothryocephalus  latus.     Hygienic  Lab.  Bull.   No.  87,  p.  250. 


OLEORESIN  OF  ASFIDIUM  03 

Aspidium  Filix-mas   Swartz. 
Aspidium  Mildeanum  Goeppert. 
Lastrea  Filix-mas  Presl. 
Nephrodium  Filix-mas  Michaux 
PolypodiAim  Filix-mas  Linne. 
Folystichum  Filix-mas  Eoth. 
Tectarea  Filix-mas  Cavan. 
Polypodium-nemorale   Salisbury, 
Folystichum  Durum  et  induratum  Schur. 
Folystichum  ahhreviatum  De  Candolle. 

In  addition  to  the  rhizomes  of  Dryopteris  Filix-mas  (Linne) 
Schott,  the  United  States  Pharmacopwia  also  permits  the  use  of 
the  rhizomes  of  Dryopteris  marginalis,  Linne  formerly  referred 
to  the  genus  Aspidium  as  Aspidium  marginale  Schwartz.  It 
should  be  noted  in  this  connection  that  the  official  recognition 
of  Dryopteris  marginalis  Linne  appears  to  have  been  based  on 
the  somewhat  doubtful  statements  of  but  three  persons  made 
back  in  the  seventies.  These  men,  Pa^tterson,^  Cressler,^  and 
Kennedy,^  respectively,  reported  that  they  had  prepared  oleo- 
resins  from  the  rhizomes  of  this  fern.  Two  of  them,  Cressler 
and  Kennedy,  also  stated  that  their  preparations  were  found  to 
be  active  in  the  expulsion  of  tape  worm,  while  Patterson  merely 
reported  that  his  preparation  resembled  the  German  oleoresin 
of  male  fern  in  appearance  and  taste.  There  does  not  appear 
to  be  any  evidence  in  the  literature  to  show  that  an  oleoresin 

f  authentically  prepared  from  this  rhizome  was  ever  given  a  trial 
by  a  reputable  physician.  Furthermore,  there  is  no  evidence 
to  the  effect  that  the  rhizome  is  ever  used  in  preparing  the 

I  oleoresin  at  the  present  time,  a  statement  which  has  also  been 
made  by  Rusby.* 

The  definition  of  Aspidium  as  given  in  the  ninth  revision  of 

ithe  United  States  Pharmacopoeia  is  as  follows:  ''The  rhizome 
and  stipes  of  Dryopteris  Filix-mas  (Linne)  Schott,  or  of 
Dryopteris  marginalis  (Linne)  Asa  Gray  (Fam.  Polypodiaceae) , 
collected  in  the  autumn,  freed  from  the  roots  and  dead  portions 
of  rhizomes  and  stipes  and  dried  at  a  temperature  not  exceed- 
ing 70°  C.  Preserve  aspidium  in  tightly  closed  containers  and 
protect  from  light. ' ' 


*Am.  Journ.  Fharm.    (1875),  47,  p.  292. 

^  Cressler  states  that  he  prepared  an  oleoresin  from  what  he  thought  to 
be  male  fern,  but  which  later  proved  to  be  Aspidium  marginale.  Ibid., 
(1878),  5,  p.  290. 

•Ibid.    (1879),  51,  p.  382. 

<Drugg.  Circ.   (1910),  54,  p.  6l6. 


'64 


DU  MEZ— THE  GALENICAL  OLEORESINS 


With  further  reference  to  the  species  of  drug  specified  by  the 
Pharmacopoeia,  it  should  be  stated  that  the  male  fern  of  com- 
merce, obtained  from  Europe,  is  frequently  contaminated  with 
the  rhizomes  of  other  species  of  fern,  principally  those  of 
Dryopteris  spinulosa  Kunze.  Pendorff  (1903),  who  examined  20 
samples  of  the  commercial  drug,  reported  that  12  of  them  con- 
tained over  50  per  cent,  of  rhizomes  of  this  species. 

The  pharmacopoeial  directions  concerning  the  collection  of  the 
rhizomes  in  autumn  are  in  keeping  with  specifications  given  in 
most  of  the  foreign  pharmacopoeias^  and  are  based  on  the  re- 
sults of  extensive  investigations  carried  out  in  continental 
Europe  and  England.  Analyses  of  the  drug  harvested  at  dif- 
ferent periods  of  the  year  have  shown  autumn  to  be  the  sea- 
son in  which  the  therapeutically  active  constituents  are  pres- 
ent in  greatest  amount.  Thus,  the  firm  of  Caesar  and  Loretz, 
in  their  Berichte  for  1898,  state  that  the  amount  of  active  con- 
stituents present  does  not  begin  to  approach  the  maximum  until 
the  month  of  August  and  that  it  again  begins  to  diminish  in 
October.  They,  therefore,  conclude  that  the  rhizomes  should 
be  harvested  only  in  the  months  of  August,  September  and 
October.  Similar  conclusions  were  drawn  by  Ed.  Schmidt^ 
from  a  series  of  observations  made  in  France  in  1903.  The  fol- 
lowing table  compiled  by  the  latter  shows  the  variation  in  crude 
filicin  content  of  the  ethereal  extracts  (oleoresins)  prepared 
from  the  rhizomes  harvested  during  six  consecutive  months  of 
the  year. 


Table  8. —  Variation  of  crude  filicin  content  due  to  season. 


Crude  filicin  content  of  oleoresins  prepared  from 
rliizomes  gathered  in  the  — 

Time  of  harvesting 

Forest  near 
Paris 

Jura 

Mts. 

Vosges 
Mts. 

Vosg-es  Mts. 
Peeled  Rhiz. 

May           

Per  cent 

9.70 
10.80 
10.86 
11.64 
13.78 
11.80 

Per  cent 

12.78 
13.86 
14.60 
17.80 
19.60 
18.68 

Per  cent 

13.76 
15.65 
17.70 
19.70 
20.76 
19.80 

Per  cent 

12.75 

July         

14.85 

Ausrust            

15.60 

17.76 

October     

16.70 

*The  Spanish  Pharmacopoeia  (1905)  directs  that  the  rhizomes  be  collected 
at  the  end  of  spring:  or  in  the  autumn. 

^  TMse  pour  Vobtention  du  Diplome  de  Docteur  de  I'Universitc  de  Paris 
•(1903),  p.  116. 


OLEORESIN  OF  ASFIDIUM  65 

The  table  not  only  shows  a  variation  in  the  crude  filicin 
content  due  to  season,  but  also  points  out  the  fact  that  there  is 
a  very  considerable  variation  due  to  the  locality^  in  which  the 
rhizomes  are  grown.  This  factor,  while  evidently  overlooked 
by  the  United  States  Pharmacopceial  Revision  Committee,  ap- 
pears to  be  of  considerable  importance  in  influencing  the  qual- 
ity of  the  oleoresin.  Further  proof  of  this  is  to  (be  found  in 
the  reports  of  Van  Aubel,^  Madsen,^  Matzdorff,^  and  Caesar 
and  Loretz/ 

Further  inspection  of  the  pharmacopoeia!  definition  shows 
that  the  official  drug  is  intended  to  be  represented  by  the  whole 
rhizome  and  stipe  deprived  only  of  the  roots  and  dead  portions, 
which  is  also  in  conformity  with  the  description  generally  found 
in  foreign  pharmacopoeias.  This  is  a  wise  provision  in  that  the 
rhizomes  not  only  contain  less  of  the  active  constituents  when 
peeled^  but  deteriorate  much  more  rapidly.  On  the  other  hand, 
compliance  with  this  specification  would  appear  to  be  a  difficult 
problem  for  the  pharmacist  as  practically  all  of  the  drug  on  the 
American  market  is  peeled.  The  latter  statement  is  based  on 
the  examination  of  a  number  of  samples  in  the  laboratory^  and 
on  the  reports  of  pharmaceutical  manufacturers^  and  others^. 

In  the  drying  of  the  rhizomes,  the  United  States  Pharmaco- 
pccia  specifies  that  the  temperature  shall  not  exceed  70  °C. 
This  temperature  is  thought  to  be  too  high,  as  filmaron,  the 
most  active  constituent  therapeutically,  melts  at  60° C  and  is 
very  prone  to  undergo  decomposition.^     The  directions  as  given 


^  A  variation  due  principally  to  soil  and  climate. 

'Van  Aubel  (1896)  states  that  the  rhizomes  growing  in  Wolmnr  on  the 
flhores  of  the  Aa  and  those  growing  in  the  Jura  and  Vosges  mountains  yield 
fl,n  oleoresin  which  is  more  active  therapeutically  than  that  prepared  from 
the  rhizomes  growing  in  Italy. 

^  Madsen  (1897)  and  Matzdorff  (1901)  report  the  oleoresin  prepared  from 
Russian  rhizomes  to  be  the  most  active. 

•  Caesar  and  Loretz  attribute  the  uniform  activity  of  the  oleoresin  pre- 
pared by  them  to  the  fact  that  they  obtain  their  supply  of  rhizomes  from 
the  same  locality  each  year. 

•  See  preceding  table  by  Schmidt. 

•  Of  the  sixteen  samples  of  male  fern  rhizomes  purchased  from  various 
«ources  in  the  United  States  and  examined  in  the  laboratory  all  but  three 
were   in  the  peeled  condition. 

^  Letters  received  from  a  number  of  pharmaceutical  manufacturers  in  this 
country   indicate  that  the  drug  as  usually  received  from  Europe  is  peeled. 

'Plaut  (1914)  states  that  though  the  U.  8.  Pharmacooepia  requires  the 
use   of  unpeeled  aspidium.,  none  such  is  to  be  found  on   the  market. 

"Kraft   (1902). 


gg  DU  MEZ— THE  GALENICAL.  OLEORESINS 

in  the  Belgian  Pharmacopoeia  (1906),  ''dry  at  a  temperature 
below  40°C,"  or  the  Norwegian  Pharmacopoeia  (1914),  ''dry 
at  a  temperature  not  exceeding  60 °C,"  appear  to  be  more 
rational. 

In  connection  with  the  pharmacopoeial  provision  concerning 
the  preservation  of  the  drug,  attention  is  called  to  the  fact  that 
the  late  edition  of  the  German  Pharmacopoeia  (1910)  requires- 
that  the  dried  rhizomes  be  kept  over  freshly  calcined  lime. 
Such  a  procedure  was  shown  by  Hager,  as  early  as  1871,  to- 
render  the  oleoresin  prepared  therefrom  less  liable  to  form  a 
deposit. 

The  fact  that  the  United  States  Fliarmacopma  does  not 
specify  a  time  limit  for  the  consumption  of  the  drug  is  unfor- 
tunate in  view  of  the  rapidity  with  which  it  is  known  to  de- 
teriorate.^ So  important  is  this  factor,  that  the  French  Phar- 
macopoeia (1908)  directs  that  only  the  recently  collected  and 
freshly  dried  rhizomes  be  employed  and  the  other  European 
pharmacopoeias  commonly  specify  that  they  be  renewed  an- 
nually. That  there  is  need  of  similar  restrictions  in  this 
country  will  become  evident  from  the  following  table  showing 
the  results  obtained  in  the  examination  of  fourteen  samples 
of  commercial  rhizomes.  Six  of  these  samples  were  purchased 
from  importers  and  drug  millers  in  the  United  States  during 
the  winter  and  spring  of  1909  and  1910,  respectively.  .  The  other 
specimens  were  received  in  January  of  1913  and  represent 
samples  obtained  from  abroad  as  well  as  in  this  country.  In 
each  case,  the  rhizomes  were  sorted,  those  showing  a  green  frac- 
ture having  been  separated  from  those  showing  an  internal 
brown  color. 


1  Peschier  as  early  as  1825  noted  that  the  therapeutic  activity  of  the 
rhizomes  diminished  on  ageing  and  recommended  that  they  should  be  con- 
sumed within  a  period  of  less  than  two  years  after  harvesting. 

Caesar  and  Loretz  state  that  they  prepare  the  year's  supply  of  oleoresin 
immediately  after  harvesting  and  drying  the  rhizomes  to  insure  the  maxi- 
mum activity  of  the  preparation. 


OLEORESIN  OF  ASPIDIUM 


67 


Table  9. — Percentage  of  green  rhizomes  in  samples  of  male  fern  purcliased 
from  drug  millers  and  jobbers. 


Sample  No. 

Date  of  purchase 

Source 

Content  of 

grreen 
rhizomes 

December,  1909 

Aoril  1910 ! '. '. 

United  States 

Per  cent. 
6.5 

2 

18.0 

m 

O.Qi 

O... 

li                        4. 

8.0 

? * 

4; 

0.0 

•1        It 

"                   " 

53.7 

2 »•.«• 

January,  1913 

44                              44 

0.0 

r, 

1.                        44 

9.2 

9'"* 

.» 

Eng'land 

0.0 

<« 

u....... 

ti                      n 

0.0 

•>           t> 

Germany 

X.'i 

in 

X6. 

»            (> 

8.5 

li           ii 

France 

0.0 

.1             >k 

0.0 

1  Composed  entirely  of  Osmunda  rhizomes. 

It  will  be  noticed  that  even  the  rhizomes  purchased  in  Ger- 
many were  not  in  good  condition.  As  these  rhizomes  were  ob- 
tained in  January,  they  should  have  shown  an  internal  green 
coloration  had  they  consisted  of  the  fresh  stock  harvested  in 
the  preceding  autumn.  From  this,  it  appears  that  the  German 
supply  for  exportation,  at  least,  is  not  renewed  yearly  as  it 
should  be,  but  is  allowed  to  accumulate  and  deteriorate. 

TJ.  S.  P.  Text  and  Comments  Thereon. 

Oleoresin  of  aspidium  was  admitted  to  the  United  States 
Pharmacopoeia  in  1870  and  has  been  official  in  all  subsequent 
editions. 


1870 

Oleoresina  Filicis 
Oleoresin  of  Fern 


Take  of  Male  Fern,*  in  fine  powder,^ 
twelve  troy  ounces;  Ether*  a  suf- 
ficient quantity. 
Put  the  male  fern  into  a  cylindri- 
cal glass  percolator,  provided  with  a 
stop-cock,    and    arranged    with    cover 
and   receptacle   suitable    for    volatile 
liquids,"  press  it  firmly,  and  gradually 


pour  ether  upon  it,  until  twenty-four 
fluidounces  of  liquid  have  slowly 
passed.'  Recover'  the  greater  part  of 
the  ether  by  distillation  on  a  water- 
bath,  and  expose  the  residue,  in  a 
capsule,  until  the  remaining  ether  has 
evaporated.'  Lastly,  keep  the  oleo- 
resin in  a  well-stopped  bottle.' 


68  DU  MEZ— THE  GALENICAL  OLEORESINS 

1880 

Oleoresina  Aspidii  ■,' 

Oleoresin  of  Aspidium 

[Oleoresina  Filicis,  Pharm.,  1870] 

Aspidium,*    in    No.    60    powder/    one  ether  by  distillation  on  a  water-bath, 

hundred   parts    100.  and  expose  the  residue,  in  a  capsule, 

Stronger  Ether,*  a  sufficient  quantity,  until  the   remaining  ether   has  evap- 

Put  the  aspidium  into  a  cylindrical  orated,* 

glass  percolator,     provided     with     a  Keep  the  oleoresin  in  a  well  stopped 

cover  and  receptacle  suitable  for  vola-  bottle*. 

tile     liquids,*     press     it     firmly,  and  Note.      Oleoresin    of    aspidium    us- 

gradually  pour  stronger  ether  upon  it,  ually  deposits,  on  standing,  a  granu- 

until  one  hundred    and    fifty    (150)  lar  crystalline  substance.**  This  should 

parts   of   liquid  have   slowly   passed.'  be  thoroughly  mixed  with  the  liquid 

Recover'     the     greater     part     of  the  portion,  before  use." 


r  1890 

Oleoresina  Aspidii 

Oleoresin  of  Aspidium 

Aspidium,*  recently'  reduced  to  No.  60  of    the    ether      from     the     percolate 

powder,*    five     hundred      grams  by  distillation  on  a  water-bath,  and, 

500  Gm.  having  transferred   the   residue  to   a 

Ether*  a  sufficient  quantity.  capsule,  allow  the  remaining  ether  to 

Put  the  aspidium  into  a  cylindrical  evaporate  spontaneously.' 
glass  percolator,  provided  with  a  stop-  Keep  the  oleoresin  in  a   well-stop- 
cock,   and    arranged    with    cover    and  pered  bottle.' 

receptacle  suitable  for  volatile  liquids."  NOTE.      Oleoresin     of     Aspidium 

Press  the  drug  firmly,  and  percolate  usually  deposits,  on  standing,  a  gran- 

slowly   with   ether,    added   in   succes-  ular-crystalline       substance.**         This 

■sive    portions,    until    the    drug  is  ex-  should  be  thoroughly  mixed  with  the 

hausted.*     Eecover    the    greater  part  liquid  portion  before  use.** 


OLBORESIN  OF  ASPIDIUM 


69 


1900 

Oleoresina  Aspidii 
Oleoresin  of  Aspidium 


Aspidium,*   recently '  reduced  to  No. 
40  powder/  five  hundred  grammes 

500  Gra. 

Acetone,*  a  sufficient  quantity. 

Introduce  the  Aspidium  into  a  cy- 
lindrical glass  percolator,  provided 
with  a  stop-cock,  and  arranged  with  a 
cover  and  a  receptacle  suitable  for 
volatile  liquids."  Pack  the  powder 
firmly  and  percolate  slowly  with  ace- 
tone, added  in  successive  portions, 
until  the  Aspidium  is  exhausted.' 
Eecover^  the  greater  part  of  the  ace- 
tone  from   the  percolate  by   distilla- 


tion on  a  water-bath,  and,  having 
transferred  the  residue  to  a  dish,  al- 
low the  remaining  acetone  to  evap- 
orate spontaneously  in  a  warm  place." 
Keep  the  oleoresin  in  a  well-stoppered 
bottle." 

NOTE.  Oleoresin  of  aspidium  us- 
ually deposits,  on  standing,  a  granu- 
lar crystalline  substance."  This 
should  be  thoroughly  mixed  with  the 
liquid  portion  before  use." 

Average  dose 2  Gm. 

(30  grains). 


1910 

Oleoresina  Aspidii 
Oleoresin  of  Aspidium 
Oleores.  Aspid. — Oleoresin  of  Male  Fern 


Aspidium,^      recently'      reduced     to 
No.     40    powder,'    five    hundred 

grammes 500  Gm. 

Ether,*  a  sufficient  quantity. 

Place  the  aspidium  in  a  cylindrical 
glass  percolator,  provided  with  a 
stop-cock,  and  arranged  with  a  cover 
and  a  receptacle  suitable  for  volatile 
liquids.''  Pack  the  powder  firmly,  and 
percolate  slowly  with  ether,  added  in 
successive  portions,  until  the  drug  is 
exhausted."  Eecover '  the  greater 
part  of  the  ether  from  the  percolate 
by   distilling   on    a   water   bath,   and, 


having  transferred  the  residue  to  a 
dish,  allow  the  remaining  ether  to 
evaporate  spontaneously  in  a  warm 
place.*  Keep  the  oleoresin  in  a  well- 
stoppered    bottle.' 

NOTE. — Oleoresin  of  Aspidium,  on 
standing,  usually  deposits  a  granular 
crystalline  substance."  This  should 
be  thoroughly  mixed  with  the  liquid 
portion   before   use." 

Average  Dose — Caution !  Single 
dose,  once  a  day.  Metric,  2  Gm. — 
Apothecaries,  30  grains. 


rjQ  DU  MEZ— THE  GALENICAL.  OLEORESINS 

1.)  The  Pharmacopoeia  of  1870  recognized  but  one  species 
of  fern  (Aspidium  Filix-mas)  as  the  source  of  the  official  drug, 
hence,  the  directions :  * '  Take  of  Male  Fern,  etc. ' '  In  the  sub- 
sequent editions,  Aspidium  marginale  was  also  recognized  as  a 
cource  of  supply.  In  these  editions,  the  drug  is,  therefore, 
referred  to  by  the  generic  name,  Aspidium.  The  species  from 
which  the  official  drug  is  obtained  are  now  referred  by  botanists 
to  the  genus  Dryopteris.  See  page  969  under  "Drug  used,  its 
collection,  preservation,  etc." 

2.)  Owing  to  the  fact  that  the  drug  deteriorates  rapidly 
when  in  the  powdered  condition,  the  last  three  editions  of  the 
Pharmacopoeia  have  specified  that  the  rhizomes  be  preserved 
whole  and  that  they  may  be  reduced  to  a  powder  shortly  before 
using.  For  factors  causing  the  deterioration  of  the  drug,  see 
under  "Drug  used,  its  collection,  preservation,  etc.'' 

3.)  In  the  last  two  editions  of  the  Pharmacopoeia,  it  is  di- 
rected that  the  drug  be  employed  in  the  form  of  a  moderately 
coarse  powder  (No.  40).  In  the  previous  editions,  a  fine  pow- 
der (No.  60)  was  specified.  The  coarser  powder  posesses  dis- 
tinct advantage  in  that  it  is  better  adapted  to  percolation  and 
can  be  produced  with  a  greater  degree  of  uniformity. 

4.)  It  will  be  observed  that  the  pharmacopoeias  of  1870,  1880 
and  1890  directed  that  the  drug  be  extracted  with  ether;  that 
acetone  was  the  menstruum  specified  in  the  Pharmacopoeia  of 
1900;  and  that  ether  is  again  directed  to  be  used  for  this  pur- 
pose by  the  present  Pharmacopoeia. 

These  changes  appear  to  have  been  made  for  economic  rea- 
sons as  is  evidenced  in  the  following  statement  by  Beringer 
(1916)  :  "In  the  Eighth  Revision,  acetone  was  directed  in  place 
of  ether,  because  at  that  time  the  former  was  cheaper.  As  it 
is  now  permissable  to  use  denatured  alcohol  in  the  manufacture 
of  ether,  that  solvent  is  made  so  cheaply  that  it  is  again  advan- 
tageous to  use  it  in  place  of  acetone. ' '  If  the  comparative  cost 
of  the  two  solvents  was  the  factor  which  induced  the  Revision 
Committee  to  make  the  last  change,  it  is  indeed  fortunate  that 
ether  was  the  cheaper  inasmuch  as  it  has  proven  to  be  the  more 
desirable  from  a  scientific  standpoint  as  well. 

Acetone,  although  the  official  menstruum  for  the  preparation 
of  this  oleoresin  for  more  than  a  decade,  does  not  appear  to 
have  been  employed  for  this  purpose  to  any  considerable  ex- 


OLEORESIN  OF  ASPIDIUM  71 

tent  by  the  manufacturer.  This  statement  is  based  upon  the 
examination  of  a  number  of  commercial  samples  purchased  at 
various  times  during  the  past  ten  years.  While  the  reason  for 
the  above  condition  does  not  become  apparent  from  the  litera- 
ture, it  is  thought  that  it  is  to  be  attributed  to  the  fact  that 
acetone  yields  a  product  of  inferior  quality,  rather  than  to  the 
relatively  low  cost  of  ether.  In  support  of  this  supposition,  at- 
tention is  called  to  the  statement  of  Dunn  (1909),  who  reports 
that  it  is  necessary  to  purify  the  oleoresin  made  with  acetone 
hy  dissolving  the  same  in  ether,  also,  to  the  observations  made  in 
the  laboratory. 

Experiments  conducted  in  the  laboratory  have  shown  that 
the  oleoresin,  when  prepared  with  acetone,  is  brown  in  color  and 
always  contains  considerable  deposited  matter.  While  the  greater 
bulk  of  the  deposited  material  has  the  appearance  of  extractive 
matter  and  is  very  likely  of  no  consequence  from  a  therapeutical 
standpoint,  portions  of  it  answer  to  the  descriptions  of  filixnigrin 
and  filix  acid,  decomposition  products  of  the  therapeutically 
active  constituents.  The  latter  observation  is  in  keeping  with 
that  of  Kraft  (1902),  who  found  that  filmaron,  the  most  im- 
portant of  the  therapeutically  active  constituents,  decomposes 
in  acetone  solution  yielding  the  above  mentioned  decomposition 
products.  It  was  also  noted  that  the  amount  of  deposited 
material  increases  much  more  rapidly  in  the  preparations  made 
with  acetone  than  in  those  in  which  ether  was  used  as  the  men- 
struum for  extracting  the  drug. 

As  previously  stated,  ether  has  proven  to  be  the  more  sat- 
isfactory solvent  for  scientific  as  well  as  economic  reasons.  In 
fact  it  has  been  found  to  be  superior  to  any  of  the  solvents 
which  have  been  experimented  with  in  this  connection,  namely: 
benzin,  benzene,  chloroform  and  carbon  disulphide.  See  Part  I, 
page  921,  under  *' Solvents."  At  the  present  time,  it  is  the  sol- 
vent universally  employed  in  the  manufacture  of  the  oleoresin, 
which  is  in  itself  a  good  reason  for  its  adoption  by  the  Pharma- 
copoeia. Furthermore,  the  product  obtained  with  ether  is 
perfectly  homogenous  and  forms  a  deposit  only  after  long 
standing,  the  constituents  of  therapeutic  value  evidently  under- 
going no  decomposition  in  ethereal  solution.  However,  the 
quality  of  the  preparation,  even  when  ether  is  employed  in  ex- 
tracting the  drug,  is  influenced  to  a  certain  extent  by  the  purity 
of  the  solvent. 

©2— S.  A.  L. 


72  I5U  MEZ— THE  GALENICAL.  OLEORESINS 

Alcohol  and  water  appear  to  be  the  impurities  which  tend 
to  exert  a  deleterious  influence  upon  the  finished  product.  Thus, 
Daccomo  and  Scoccianti  (1896)  observed  that  ether  containing- 
a  considerable  amount  of  alcohol  did  not  completely  extract  the 
therapeutically  active  constituents  from  the  drug  and  that  the 
oleoresin  obtained  was  more  prone  to  form  a  .deposit  than  when 
ether  of  a  greater  degree  of  purity  was  used.  See  also  page  984 
ander  ''Yield  of  oleoresin."  Similar  effects  were  observed 
by  the  firm  of  Caesar  and  Loretz  (1899.)  The  presence  of 
water  is  so  great  a  factor  in  promoting  decomposition 
(hydrolysis?)  that  the  German  Pharmacopoeia  (1910)  directs 
that  the  rhizomes  be  preserved  over  freshly  burned  lime,  a 
procedure  which  was  recommended  by  Hager  as  early  as  1871. 
Further  evidence  of  the  undesirability  of  the  presence  of  water 
is  to  be  found  in  the  Norwegian  (1913)  and  Finnish  (1914) 
pharmacopoeias,  which  direct  that  the  ethereal  tincture  be  dried 
with  anhydrous  sodium  sulphate  or  fused  calcium  chloride  pre- 
vious to  the  removal  of  the  solvent  by  distillation. 

5.)  For  a  description  of  the  various  forms  of  percolators 
designed  for  extraction  with  volatile  solvents,  see  Part  I  under 
''Apparatus  used." 

6.)  All  editions  of  the  Pharmacopoeia,  including  the  present,, 
direct  that  the  drug  be  extracted  by  the  process  of  simple  per- 
colation even  though  the  advantages  of  a  continuous  extraction 
apparatus  in  the  handling  of  a  volatile  solvent  like  ether  have 
been  repeatedly  pointed  out.  See  Part  1  under  "Solvents" 
and  under  "Apparatus  used." 

Of  special  interest  in  this  connection  is  the  work  of  Matzdorif 
(1901),  the  results  of  which  show  that  the  therapeutically  ac- 
tive constituents  are  not  completely  extracted  by  simple  perco- 
lation as  ordinarily  carried  out,  but  that  complete  extraction 
is  effected  in  a  comparatively  short  time  with  the  use  of  a  Soxh- 
let's  apparatus. 

7.)  In  connection  with  the  recovery  of  the  solvent  by  dis- 
tillation, attention  is  again  directed  to  the  deleterious  effect  of 
the  presence  of  moisture  and  to  the  manner  in  which  the  same 
is  directed  to  be  removed  by  the  Norwegian  and  Finnish  phar- 
macopoeias.     See  above. 

Attention  is  also  invited  to  the  pharmacopoeial  directions  re- 
garding distillation,  namely  that  it  be  conducted  on  a  water 


OLEORESIN  OF  ASFIDIUM  73 

bath.  Inasmuch  as  Kraft  (1902)  states  that  filmaron  melts 
at  60°C  and  undergoes  decomposition  at  higher  temperatures, 
it  is  thought  that  the  pharmacopoeial  directions  should  contain 
a.  warning  against  exceeding  this  temperature  during  distilla- 
tion. 

8.)  The  removal  of  a  part  of  the  solvent  by  spontaneous 
evaporation  as  directed  by  the  Pharmacopoeia  tends  to  operate 
against  obtaining  a  uniform  product  as  the  time  required  to 
accomplish  the  same  varies  mth  the  temperature.  If  evapora- 
tion is  allowed  to  proceed  at  a  low  temperature  (winter  tem- 
perature), the  preparation  will  be  exposed  to  the  action  of  the 
air  for  a  very  considerable  length  of  time  and  partial  oxida- 
tion of  some  of  the  constituents  will  very  likely  result. 

The  complete  removal  of  the  solvent  can  be  accomplished 
much  more  rapidly  by  heating  the  preparation  on  a  water  bath, 
and  without  injury,  if  the  temperature  is  kept  below  60° C.  By 
such  a  procedure,  the  above  conditions  are  eliminated  and  a  more 
uniform  product  will  be  obtained. 

9.)  The  oleoresin  should  be  kept  in  well-stoppered  bottles 
as  it  becomes  rancid  on  prolonged  exposure  to  the  air  due  to 
the  hydrolysis  and  partial  oxidation  of  the  glycerides  composing 
the  fatty  oil. 

10.)  For  a  discussion  of  the  nature  of  the  deposit  which 
forms  in  the  oleoresin  on  standing,  see  pages  992  and  1004  under 
■''Constituents  of  therapeutic  importance,"  and  under  ''Other 
properties. ' ' 

11.)  As  to  the  propriety  of  the  pharmacopoeial  directions 
concerning  the  mixing  of  the  deposit  with  the  liquid  portion 
before  dispensing,  there  is  some  doubt.  The  question,  however, 
is  one  which  should  be  decided  by  the  pharmacologist  rather 
than  the  pharmacist  and  will,  therefore,  not  be  considered  here. 

The  use  of  an  alkali,  ammonia  as  suggested  by  Beringer 
(1892),  for  the  purpose  of  facilitating  the  admixture  of  the  pre- 
cipitate with  the  liquid  portion  should  be  condemned  as  a  dan- 
gerous practice.  The  danger  lies  in  the  fact  that  the  slightly 
soluble  toxic  constituents  are  converted  into  soluble  compounds 
by  union  with  the  alkali  and  are  thereby  rendered  readily  ab- 
sorbable. 

Of  further  interest  in  this  connection  is  the  procedure  recom- 
mended by  Seifert   (1881)   and  Kraemer   (1884)   for  avoiding 


74  DU  MEZ— THE  GALENICAL.  OLEORESINS 

the  formation  of  a  deposit,  namely:  that  the  ethereal  tincture 
be  kept  on  hand  and  that  the  oleoresin  be  prepared  therefrom 
just  previous  to  dispensing. 

Yield 

The  yield  of  oleoresin,  when  ether  is  the  solvent  employed 
in  extracting  the  drug,  is  commonly  stated  to  be  10  to  15  per 
cent,  in  the  various  dispensatories  and  American  text-books  on 
pharmacy.  As  a  matter  of  fact,  the  amount  of  oleoresin  actually 
obtained  is  about  7  to  10  per  cent.  (See  the  tables  which  fol- 
low.) When  petroleum  ether  or  benzene  is  used,  the  yield  m 
slightly  lower,  as  a  rule,  whereas,  it  is  much  higher  (about  18 
per  cent.)  when  acetone  is  employed.  These  statements  refer 
to  the  yield  as  found  for  the  air  dried  drug.  When  the  latter 
is  dried  at  a  temperature  of  100  to  110° C,  the  percentage  of 
oleoresin  obtained  will  naturally  be  somewhat  higher  as  is  shown 
in  the  table  immediately  following. 


OLEORESIN  OP  ASPIDIUM 


75 


Table  10.  —  Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  oleoresin  to 

Date 

< 

1 

1 

CO 

J 

Remarks 

1826 

von  Esenbeck . 

Van  Dyk  

Zeller 

Perct. 

Per  ct. 

Perct. 
5.63 
7.30 

Perct. 

Rhizomes     harvested      in 

1827 

37.5 
32.0 

August. 
Rhizomes  harvested  in 

1828 

Meylink 

6.04 

September. 

Winkler 

Haendess 

15.6 

Rhizomes  harvested  in 

1829 

8.85 

8.33 

12.87 

7.80 

8.20 
8.50 

10.30 

12.40 

11.50 

14.00 

6.51- 
5.60 

6.20 

5.70 

6.00 

8.50 
8.00 

11.00 
13.00 
6.00 
6.50 
5.70 

9.87 
7.26 
8.90 
5.90 

6.12 

8.92 

9.96 

9.50 

9.88 



February. 

1844 

1851 

Bock       

Peeled   rhizomes    dried  at 

1852 

von  der  Marck 

100°  c. 
Portion  of  rhizomes  having 

borne  fronds  the  previous 
year. 
Portion  of  rhizome  bearing 

fronds. 
Portion   of  rhizome  to  de- 

1876 

r  Petrol. 
1  Etlier 

1      '-' 

1       9.1 

I 

velop  fronds  the  next  year. 
Rhizomes  harvested  in 

Kremel 

Trimble 

April.  Dried  at  110°  C. 
Rhizomes  harvested  in  July 

Dried  at  110°  C. 
Rhizomes  harvested  in  Oc- 

1887 

29.0 

tober.    Dried  at  110°  C. 

1888 

J  Benzin 

1      5.9 

1891 

Nagrelwoort  (i) 

Rhizomes  harvested  in 

July.  1889. 
Rhizomes  harvested  in 

September,  1889. 
Rhizomes  harvested  in 

October,  1889 
Rhizomes  harvested  in 

December. 

Rhizomes  harvested  in 



February,  1890.^^ 

"                      "       •' 

Rhizomes  harvested  in 

April.  1890. 

1892 

18.0 

j  Benzin 
1     16.18 

" 

Sherrard 

Whole  Rhizomes. 

Bellingrodt . . . 

Peeled 

1898 

Rhizomes  from  "Rheinische 

Tiefebene  (Calcar)." 
Rhizomes  from  "'Rheinische 

Tiefebene  (Dinslaken)." 
Rhizomes   from    "Voreifel 

(Aachen.)" 
Rhizomes  from  "Hocheifel 

(Gerolstein.)" 
Rhizomes    from     "Taunus 

(Braubach.)" 
Rhizomes    from      Wester- 

wald    auf     Thonschiefer 
(Daaden.)"                  ^—^ 

'  Ed.  Schmidt,  Th&se  pour  I'Obtention 
Paris,  1903,  p.  78. 


du  DiplOme  du  Docteur  I'UnlverslW 


76 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


Table  10.— Continued. 


Date 


1902 
1903 


1905 


1906 


1906 


Observer 


Bellingrodt— 
Con. 


Hausmann 


Buttin 

Schmidt.  E.(») 


Dietrich 


Roder 


Wollenweber. 


Yield  of  oleoresin  to 


Perct. 


Perct. 


Perct. 
9.95 

8.90 
8.50 
10.00 
8.00 
9.30 
8.00 
6.60 

9.60 

9.10 

6.40 

6.90 

9.80 

9.30 

7.00 


9.94  to 
10.60 

Up  to 
11.20 

9.22  to 
10.1 


10.30 
10.00 


Per  ct. 


Benzene 
!    9.81 


10.10 


Petrol. 
Ether 


9.5 


Remarks 


Rhizomes  from  "Wester- 

wald   auf  Basalt  boden 

(Daaden.)' 
Rhizomes  from  "Hansruclc 

(Simmern) ' 
Rhizomes  from  "St.Gallen, 

Switzerland." 
Rhizomes   from   "Bludenz 

(Vorarlberg)." 
Rhizomes  from  "Appenzell, 

Switzerland." 
Rhizomes   from    "Bierber- 

wier,  Tyrol." 
Rhizomes  harvested   in 

spring:. 
Whole  rhizomes  from  near 

Paris   harvested   in  Sep- 
tember. 
Whole  rhizomes  from   the 

Vosges  JVIts.  harvested  in 

September. 
Whole  rhizomes   from   the 

Jura  Mts.    harvested    in 

September. 
Peeled  rhizomes   from  the 

Vosges  Mts.  harvestsd  in 

September. 
Whole  rhizomes  from  near 

Paris    harvested  in   Oc- 
tober. 
Whole  rhizomes  from    the 

Vosg-es  Mts.  harvested  in 

October. 
Whole   rhizomes   from  the 

Jura  Mts.    harvested    in 

October. 
Peeled  rliizomes   from  the 

Vosges  Mts.  harvested  in 

October. 
From  air  dried  rhizomes. 

From  rliizomes  dried  at 
100°  C. 

Yield  obtained  when  the 
product  was  heated  at 
95°  C  for  2  hours,  cooled 
in  a  desiccator  &  weighed . 

Air  dried  rhizomes  extract- 
ed in  a  Soxh let's  appar- 
atus. 

Exiccated  rhizomes  ex- 
tracted in  a  Soxhlet's 
apparatus. 


Air  dried  rhizomes  extract- 
ed in  a  Soxhlet's  appar- 
atus. 

Exiccated  rhizomes  ex- 
tracted in  a  Soxhlet's 
apparatus, 


1.  c,  p.  110. 


OLBORESIN  OF  ASPIDIUM 


77 


Table  10. —Continued. 


Observer 

Yield  of  oleoresin  to 

Date 

< 

1 
§ 
< 

Si 

Other 
solvents 

Remarks 

1908 

Vanderkleed(i) 
Vanderkleed . . 

Perct. 

Perct. 

Per  ct. 

Per  ct. 

r  Solvent? 

6.68 
\     10.003 
1     17.90 
I    10.33 

Reported  as  yield  of  oleo- 

resin. 

1999 

1911 

Rosendahl.  ... 

10.00 

12.50 

11.50 

9.50 
11.60 
8.80 
7.90 
8.30 
7.70 
9.70 
8.60 

7.50 

7.00 

10.90 

9.40  to 

9.70 

Rhizomes   harvested  in 

Harrison  &  Self 
Riedel 





May. 
Rhizomes  harvested  in 

August. 

1913 

October. 
Rhizomes  from  "Harz." 

i»             .< 

H                                t( 

.1                                   41                                    .4 

"             *'        "Bayem" 

(k             ((             .1. 

(  "Schwarz- 
" "!  wald,  Wuert- 

f  em  berg." 
i  "Mo&el, 
"              *'  ■{  Rhein- 

rPreussen." 

914 

" 

Vanderkleed . . 

i  Solvent  ? 
\     6.85  to 
\     10.12 

Average  yield   of  oleoresin 
is  reported  as  8. 23  per  cent. 

^  The  high  yield  (1.79  per  cent.)  obtained  in  this  instance  is  suggestive  of 
the  use  of  acetone  as  the  menstruum  for  exhausting  the  drug.  It  may,  how- 
ever, have  been  due  to  the  extensive  adulteration  of  the  latter  with  the- 
rhizomes  of  Dryopteris  spinuloaa.  Rosendahl  (1911)  obtained  17.0  per  cent., 
of  oleoresin  from  the  rhizomes  of  this  species  by  extraction  with  ether. 

Table  11. — Yield  of  oleoresin  obtained  in  the  laboratory. 


Observer 

Yield  of  oleoresin  to 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Benzin 

Remarks 

1909 

DuMez  &  Baker 

Per  ct. 

Per  ct. 
18.27 

Per  ct. 
9.3 

9.7 

8.70 

Per  ct. 

Represents  the   yield 
using  a  Soxhlet's  ex- 
traction apparatus. 

Represents  the   yield 
using  a  Soxhlet's  ex- 
traction apparatus. 

Represents    the  yield 
using  a  Soxhlet's  ex- 
traction apparatus. 

DuMez&Beedle.... 



1910 

DuMez  &Netzel 

43.33(1) 

16.10 

7.5 

(i)The  alcoholic  extract  was  obtained  by  simple  percolation. 


78 


DU  MEZ— THE  GALENICAL  OLEORESINS 


An  examination  of  the  first  of  the  foregoing  tables  reveals 
the  fact  that  the  yield  is  influenced  to  a  very  considerable  extent 
by  the  condition  of  the  drug  from  which  the  oleoresin  is  pre- 
pared. Thus,  for  instance,  the  amount  obtained  is  less  when  the 
powdered  whole  rhizomes  are  used  than  when  peeled  rhizomes 
are  employed.  This  is  to  be  expected  in  view  of  the  fact  that 
the  outer  layers  contain  little  that  is  soluble  in  the  solvent 
(ether)  usually  made  use  of.  It  will  also  be  noticed  that  na- 
tural causes,  such  as,  locality  in  which  the  rhizomes  are  grown, 
and  time  of  harvesting  are  important  factors  in  this  connec- 
tion. These  influences  will  be  brought  out  more  clearly  on  an 
inspection  of  the  following  table  which  shows  the  results  of  this 
nature  obtained  by  Ed.  Schmidt. 

Table  12.  —  Effect  of  locality  in  which  the  rhizomes  are  gr0wn  and  the  time 
of  harvesting  on  the  yield  of  oleoresin. 


Time  of  harvesting 


May 

June 

July 

Autrust 

Peptembet 
October . . . 


Peeled  rhizomes  from- 


Forest 
near  Paris 


Per  cent. 

4.00 
4.80 
5.60 
6.20 
6.60 
6.90 


Vosges 

Mts. 


Per  cent. 

7.00 
7.60 
8.70 

g.oo 

9.60 
9.80 


Jura  Mts. 


Per  cent. 

6.40 
7.00 
8.00 
8.40 
9.10 
9.30 


Whole 

rhizomes 

from— 


Vosges 
Mts. 


Per  cent. 


4.90 
5.70 
6.00 
6.40 
7.00 


In  addition  to  the  comments  already  made  with  regard  to  the 
influence  of  the  solvent  on  the  yield,  the  observations  of  Dac- 
como  and  Sccocianti  (1896)  are  of  importance  in  this  connec- 
tion. These  investigators  found  that  the  amount  of  oleoresin 
obtained,  when  ether  was  employed  for  extracting  the  drug,  de- 
pended to  some  extent  on  the  purity  of  the  former.  Thus, 
ether,  specific  gravity  0.720  gave  10  per  cent,  of  oleoresin, 
whereas,  ether,  specific  gravity  0.756  yielded  17  per  cent.  It 
was  further  pointed  out,  however,  that  the  greater  yield  was 
not  desirable  as  in  this  case  the  preparation  did  not  contain 
all  of  the  therapeutically  active  constituents  and  in  addition 
was  more  prone  to  form  a  deposit  on  standing. 


OLEORESIN  OF  ASPIDIUM  79 

Chemistry  of  the  Drug  aTid  Oleoresin. 

Tabulation  of  Constituents, 

A  survey  of  the  voluminous  literature^  pertaining  to  the 
chemistry  of  the  mak  fern  rhizome  shows  the  constituents  of 
pharmaceutical  interest  to  be  as  follows:  volatile  oil,  fatty  oil, 
iilix  acid,  albaspidin,  flavaspidic  acid,  aspidinol,  flavaspidinin 
(phloraspin),  filmaron,  filixnigrin,  chlorophyll,  filix  tannic  acid, 
wax,  sugar,  starch  and  inorganic  constituents.  Of  these  sub- 
stances, the  following  have  been  identified  in  the  oleoresin  ob- 
tained by  extracting  the  drug  with  ether: 

Volatile  oil  =*   0.40  to     0.45  per  cent 

Fatty  oiP  70.00  to  75.00  "  '* 

Filix  acid*    5.75  to  12.48  "  '' 

Albaspidin'^    Av.  0.05  "  '' 

Flavaspidic  acid »   "  2.50  "  " 

Aspidinol »    "  0.10  ''  '* 

Flavaspidinin"   **  O.IO  "  **   * 

Filmaron*   "  5.00  "  '' 


^  The  following  have  reported  more  or  less  complete  analyses  of  the  male 
fern  rhizome  or  of  the  ethereal  extract :  Gebhardt,  cited  by  Geiger,  Mag.  f. 
Pharm.  (1824),  7,  p.  38;  Morin,  Journ.  de  Pharm,  et  de  Chim.  (1824),  10, 
p.  223;  Buchner,  Rep.  f.  d.  Pharm.  (1827),  27,  p.  337;  Batso,  TrommsdorfE's 
n.  Journ.  d.  Pharm.  (1827),  14,  p.  294;  Peschier,  Ibid.  (1828),  17,  p.  9; 
Luck,  Jahrb.  f,  prakt.  Pharm.  (1851),  14,  p.  129  ;  Bock,  Arch.  d.  Pharm. 
(1851),  115,  p.  257;  Kruse,  Ibid  (1876),  209,  p.  24;  Daccomo,  Annali  di 
Chim  et  Farmak.  (1887),  87,  p.  69;  Boehm,  Arch.  f.  Exp.  Path.  u.  Pharmak. 
(1896),  38,  p.  35;  Kraft,  Schweiz.  Wochenschr.  f.  Chem.  u.  Pharm.  (1902), 
40,  p.  322. 

'  The  percentage  of  volatile  oil  as  given  above  has  been  computed  on  the 
basis  of  an  average  yield  of  10  pr  cent,  of  oleoresin. 

3  The  quantity  of  fatty  oil  present  in  the  oleoresin  has  been  shown  to  vary 
•with  the  strength  of  the  ether  employed  in  extracting  the  drug  and  with 
the  degree  to  which  the  latter  has  been  exhausted.  These  factors,  however, 
are  not  sufficient  to  explain  the  large  variation  in  oil  content  as  found  by 
various  investigators.  The  variation  is  more  probably  due  to  the  different 
methods  employed  in  its  estimation.  Thus,  Bock  reports  the  presence  of 
42  per  cent  of  fatty  oil,  Arch.  d.  Pharm.  (1851),  115,  p.  266;  Kremel  esti- 
mates it  at  40  to  45  per  cent,  Pharm.  Post  d.  Pharm.  (1887),  20,  p.  525; 
IVollenweber  at  70  to  75  per  cent.  Arch.  d.  Pharm.   (1906),  244.  p.  467. 

*  There  is  a  very  considerable  difference  in  the  filix  acid  content  of  the 
oleoresin  as  reported  in  the  literature.  This  is  due,  principally,  to  the  nat- 
ural variation  in  the  filix  acid  content  of  the  drug  and  to  the  different 
methods  employed  in  its  estimation.  The  limits  as  given  above  are  those 
obtained  by  the  method  of  Fromme  and  represent  the  percentage  occuring 
In  the  oleoresin  prepared  from  the  better  rhizomes.  Under  these  conditions, 
Madsen  found  5.8  to  12.1  per  cent.  Arch.  f.  Pharm.  og.  Chem.  (1897),  54, 
p.  269;  Gehe  &  Co.,  5.78  to  11.32  per  cent,  Handels-Ber.  (1897),  p.  60; 
Bellingrodt,  5.75  to  10.75  per  cent,  Apoth.  Ztg.  (1898),  13,  p.  869;  Caesar 
and  Loretz,   8.65   to  12.48   per   cent,    Geschaefts-Ber.    (1901),   p.    68. 


gQ  DU  MEZ— THE  GALENICAL  OLEORESINS 

Filixnigrin  =   "       "     6.00  "  " 

Chlorophyll  • ' '  " 

Wax '     ''  " 

Ash    ''  3.50  to  5.00  ''  " 

Occurrence  and  Description  of  Individual  Constituents. 

Volatile  oil.^  The  volatile  oil  as  described  by  Ehrenberg  is 
a  clear  yellow  liquid  having  a  specific  gravity  of  0.85  to  0.86 
at  15° C,  and  is  stated  by  him  to  be  composed  principally  of 
fatty  acid  esters  of  hexyl  and  octyl  alcohol,  the  acids  ranging 
from  propionic  to  caproic. 

The  quantity  of  essential  oil  present  in  the  rhizomes  is  stated 
to  vary  with  the  seasons  of  the  year,  0.04  to  0.045  per  cent,  being 
contained  therein  at  the  time  of  the  year  when  the  drug  is- 
usually  collected.^ 

Fatty  oil}^  The  fatty  oil  as  obtained  from  the  male  fern 
rhizomes  by  extraction  with  ether  and  subsequent  purification 
is  stated  by  Katz^^  to  be  composed  of  the  glyceryl  esters  of  oleic^ 
palmitic,  cerotic  and  butyric  acids.^^ 

Filix  acid^^    (Filiciny*    Filix  acid    (CggHggOig)    crystalizes 


» Kraft,  Schweiz.  Wochenschr.  f.  Chem.  u.  Pharm.   (1902),  40.  p.  323. 

•Bock,  Arch.  d.  Pharm.   (1851),  115,  p.  266. 

T  Kraft,  1.  c, 

*  The  volatile  oil  as  described  above  is  that  obtained  from  the  rhizomes 
by  steam  distillation  and  in  all  probabilities  differs  somewhat  from  the  same 
as  it  exists  in  the  galenical  oleoresin. 

» Ehrenberg  reports  the  presence  of  volatile  oil  as  follows :  rhizomes 
gathered  in  April,  0.008  per  cent;  in  June  .025  per  cent;  in  September,  Octo- 
ber and  November,  0.04  and  0.045  per  cent.  Arch.  d.  Pharm.  (1893),  231, 
p.  345. 

10  The  fatty  oil  of  male  fern  was  probably  first  isolated  by  Luck.  In 
1851,  he  reported  that  the  oily  portion  (filixoline)  of  the  ethereal  extract 
was  a  glyceride  yielding  filomysilsaeure  and  filixoUnsaeure  upon  saponifi- 
cation.    Jahrb.  f.  prakt.  Pharm.   (1851),   22.  p.  130. 

From  Luck's  description  it  is  considered  that  these  acids  were  in  all 
probability  butyric  and  oleic,  respectively. 

"Arch.  d.  Pharm.    (1898),  236,  p.  655. 

"  Butyric  and  oleic  acids  have  also  been  identified  by  Farup  in  the  fatty 
oil  obtained  from  Aspidium  Spinulosum.  In  addition  a  phytosterol,  lino- 
linic,  and  probably  isolinolinic  acid  are  stated  to  have  been  detected.  Arch, 
d.  Pharm.   (1904),  242,  p.  17. 

"The  term  filixsaeure  was  first  used  by  Luck  to  designate  this  constituent, 
Filix  acid  is  the  translation  given  above  rather  than  the  usual  English 
form,  filidc  acid,  to  avoid  confusion  with  the  fiUcinsaeure  of  Boehm,  a  re- 
duction product  of  the  former,  Ann  .d.  Chem.  (1899),  307,  p.  249,  or  the 
Acidum  fiUceum  of  Batso,  a  supposedly  volatile  acid  which  the  latter  isolated 
from  the  ethereal  extract.  Tromsdorff's  n.  Journ.  d.  Pharm.  (1827),  14, 
p.  249. 

"  Filicin  is  the  term  introduced  by  Poulsson  to  designate  the  crystalline 
form  of  filix  acid  as  he  was  of  the  opinion  that  it  also  existed  in  the  amor- 


OLEORESIN  OF  ASPIDIUM 


81 


in  small  yellow  plates  melting  at  184  to  185°  C.  It  is  difficulty 
soluble  in  water,  alcohol,  and  ether,  quite  readily  soluble  in 
ethyl  acetate.  According  to  Boehm,^^  its  constitution^^  is  prob- 
ably represented  by  the  following  structural  formula : 


H0C|^      jIoh: 

H,C,COcL  ]iC 

COH 


Filix  acid  has  been  found  to  be  present  in  the  male  fern 
rhizome^^  in  quantities  varying  from  0.268  to  2.159  per  cent^ 
the  variation  in  content  depending  principally  upon  the  loca- 
tion in  which  the  rhizomes  are  grown  and  on  the  time  of  har- 
vesting.^^ 


phous  state.  Arch.  f.  Exp.  Path.  u.  Pharm.  (1895),  p.  357.  The  term  is  now 
usually  employed  to  designate  the  mixture  of  acid  substances  obtained  in 
the  quantitative  evaluation  of  the  oleoresin.  It  should  not  be  confused 
with  the  Filicina  of  Batso,  supposedly  an  alkaloid  isolated  from  the  ethereal 
extract.     1.  c. 

"Ann.  d.   Chem.    (1901),   318,  p.  256. 

!•  The  following  investigators  have  contributed  work  on  the  constitution 
of  fllix  acid:  Luck,  Ann.  d,  Chem.  (1845),  54,  p  119;  Jahrb.  f.  prakt. 
Pharm.  (1851),  22,  p.  129;  Grabowski,  Ann.  d.  Chem.  (1867),  143,  p.  279; 
Daccomo,  Ber.  d.  deutsch.  Chem.  Gesell.  (1888),  21,  p.  2962;  Gaz.  Chim. 
Ital.  (1895),  24,  1,  p.  511 ;  Ibid.  (1896),  26,  2,  p.  441 ;  Paterno,  Ber.  d.  deutsch. 
Chem.  Gesell.  (1889),  22,  p.  463;  SchifC,  Ann.  d.  Chem.  (1889),  253,  p.  236; 
Poulsson,  Arch.  f.  Exp.  Path.  u.  Pharm.  (1895),  35,  p.  97;  Boehm,  Ibid. 
(1897),  38.  p.  35;  Ann.  d.  Chem.  (1898,  302,  p.  171. 

"  Fllix  acid  has  also  been  isolated  by  Hausmann  from  Athyrium  Filix 
femma  Roth.  Arch.  d.  Pharm.  (1899),  237.  p.  556,  and  has  been  identified 
by  Bowman  in  Aspidium  rigidum  Swartz.  Am.  J.  Pharm.    (1881),  53,  p.  389.' 

"MatzdorfC,  Apoth.  Ztg.    (1901),  16,  p.  274. 


«2 


DU  MEZ— THE  GAKENICAL  OL.EORBSINS 


Alhaspidin}^  Albaspidin  crystallizes  in  fine  colorless  needles 
melting  at  147  to  148° C.  It  is  readily  soluble  in  ether,  chloro- 
form and  benzol,  difficultly  soluble  in  alcohol,  acetone  and 
^glacial  acetic  acid.  Its  constitution  is  stated  to  be  represented 
by  one  of  the  three  following  formulae  :^^ 


ac   cHi 


HOC 


H3C   CH, 

X 


H3C   CH, 


CO 


oc 


H,C.C0CI^  /^  V 


COH 
COCQH, 


COH     CH, 


COH 


COH 


CH, 


Flavaspidic  acid.  Flavaspidic  acid  (C24H28O8)  was  first 
isolated  from  the  ethereal  extract  by  Boehm.  It  is  stated  to 
€xist  in  two  forms  (a  and  j8)  which  differ  in  their  melting  points, 
the  a-fiavaspidic  acid  melting  at  92°  C  and  the  ^-modification  at 
156  °C.     The  a-acid   on  heating  is   converted   into  the  j8-acid 


^»  Albaspidin  should  not  be  confused  with  aspidin.  Hausmann  has  shown 
the  latter  to  be  a  constituent  of  Dryopteris  spinulosa  O.  Kuntze,  but  that 
it  Is  not  present  in  Dryopteris  filix  mas  Schott.  Arch.  d.  Fharm.  (1899), 
237,  p.  544. 

*>  Boehm,  Arch.  f.  Exp.  Path.  u.  Pharm.  (1897),  38,  p.  35;  Ann.  d.  Chem. 
<1901),  318,  p.  268. 


OLEORESIN  OF  ASPIDIUM 


83 


which  may  be  crystallized  from  hot  benzol  or  glacial  acetic  acid. 
The  ^-form  is  converted  into  the  a-modification  on  crystallizing 
the  former  from  alcohol.  The  a-acid  is  thought  to  be  the  enol-, 
the  /8-acid  the  keto-form.  The  structure  is  shown  in  the  fol- 
lowing formulae  :^^ 

c"»  cocn^5 

c 


H,C,CO 


COH 


CCH, 


HjCCOG 


CH, 
o(-F)ava5pidicAdd 


y3  f^ffavaspidkAdH 


COHJ 


Flavaspidic  acid  has  been  isolated  from  the  male  fern  rhi- 
zome in  quantities  varying  from  0.10  to  0.15  per  cent.^^ 

Aspidinol.  Aspidinol  (CiaHigO^)  crystallizes  in  small  yel- 
lowish-white needles  melting  at  156  to  161  °C.  It  is  difficultly 
soluble  in  petroleum  ether  and  benzol,  readily  soluble  in  ether, 
alcohol,  chloroform,  carbon  disulphide  and  acetone.  The  fol- 
lowing two  formulae  have  been  suggested  by  Boehm  as  repre- 
senting the  structure  of  this  compound  :^^ 


CH. 

CH^ 

A 

p. 

HOCf 

^^ 

\C0CH. 

HOC 

Voj 

HC^ 

V 

^COCC.M> 

H,CX^OC 

V 

JcH 

COH  COH 

Flavaspidinin.^*      Flavaspidinin  closely  resembles  flavaspidic 


« Boehm,  Ann.  d.  Chem.    (1901),  318,  p.   253";  Ibid.    (1903,  329,  p.  310. 

2*  In  addition  to  establishing  the  presence  of  flavaspidic  acid  in  the  male 
fern  rhizome,  Hausmann  has  also  isolated  this  compound  from  Athyrium 
JF'ilix  femina  Roth,  and  Aspidium  apinulosum  Swartz.  Arch.  d.  Pharm.  (1899), 
237,   p.   556. 

28  Arch.  f.  Exp.  Path.  u.  Pharm.  (1893),  33,  p.  35;  Ann.  d.  Chem.  (1901), 
■318,  p.  245;  Ibid.    (1903),  329.  p.   286. 

« Kraft.    Schweiz.   Wochenschr.   f.   Chem.   u.   Pharm.    (1902),    40,   p.    323. 

The  "phloraspin"    (C^^H^O^)    of  Boehm  is  probably  identical  with  flavas- 

-pidinin.     The  pale  yellow  crystals  obtained  from  the  alcoholic  solution  melt 

at  211  "C,  and  are  stated  to  be  almost  insoluble  in   ether,  petroleum   ether, 

benzene  and  carbon  disulphide,  but  more  readily  soluble  In  acetone,  chloro- 

torm,   hot    absolute   alcohol,   ethyl   acetate,    glacial   acetic   acid   and   boiling 

xylene.     Ann.  d.  Chem.    (1903),  329,  p.  338. 


84 


DU  MEZ— THE  GALENICAL.  OLBORESINS 


acid.  It  crystallizes  from  ethyl  acetate  in  nearly  colorless 
prisms  melting  at  199° C.  It  is  soluble  in  methyl  alcohol,  dif- 
ficultly soluble  in  ether,  carbon  disulphide  and  alcohol,  readily 
soluble  in  warm  benzene,  chloroform,  ethyl  acetate,  acetone  and 
amyl  alcohol. 

Filmaron,^^  Filmaron  (C^THggOis)  is  a  light  yellow,  amor- 
phous powder  melting  at  about  60° C.  It  is  insoluble  in  water,, 
difficultly  soluble  in  alcohol,  methyl  alcohol  and  petroleum  ether^ 
readily  soluble  in  acetone,  chloroform,  ether,  ethyl,  acetate,- 
benzene,  carbon  disulphide,  carbon  tetrachloride,  amyl  alcohol 
and  glacial  acetic  acid.  In  acetone  solution,  at  ordinary  tem- 
peratures' or  upon  warming  with  alcohol,  it  gradually  decom- 
poses into  filix  acid  and  filixnigrin.  The  following  structural 
formula  has  been  suggested  by  Kraft: 


COH 


Filixnigrin.^^  Filixnigrin  is  the  term  used  by  Kraft  to  desig- 
nate the  mixture  of  brown  to  black  amorphous  decomposition, 
products  of  the  foregoing  constituents.  These  decomposition 
products  differ  from  the  mother  substances  in  that  they  are  in- 
soluble in  petroleum  ether.  They  have  been  isolated  from  the- 
etheral  extract.  To  what  extent  they  occur  in  the  plant,  if  at 
all,  has  not  been  determined. 

Chlorophyll.  The  green  coloring  matter  of  the  male  fern 
rhizome  and  of  the  oleoresin  prepared  therefrom  is  generally^ 
conceded  by  the  various  investigators  to  be   chlorophyll,   al- 


»  Kraft,  1.  c. 
»« Kraft,  I.  c. 


OLBORESIN  OF  ASFIDIUM  85 

though,  no  attempt  appears  to  have  been  made  to  determine  its 
composition.  Work  upon  the  pigments  present  in  a  closely 
related  species  of  fern,  Aspidium  Filix  femina  Roth,  has  re- 
•sulted  in  the  isolation  of  carrotin  (CigHggO)  and  three  aspi- 
■diophylls,    CaogHg^^OgaN,   C24oH32o03iN2    and    C2ioH34e048N2o " 

The  amount  of  chlorophyll  present  in  the  rhizome  varies 
with  its  age  and  with  the  season  of  the  year.^^ 

Wax.  The  wax  occurring  in  the  male  fern  rhizome  has  not 
been  studied  from  a  chemical  standpoint,  although  its  presence 
in  the  ethereal  extract  was  observed  at  a  very  early  date.^^ 

Filix  Tannic  Acid.^^ '  Filix  tannic  acid  (C41H48NO24)  is  a 
^glucoside  breaking  down  upon  hydrolysis  into  hexose  and  a 
Tiiixture  of  reddish-brown  compounds.^^  It  is  readily  soluble 
in  water  and  dilute  alcohol. 

Filix  tannic  acid  usually  constitutes  about  7  per  cent,  of 
the  rhizome,  as  much  as  7.8  per  cent,  having  been  isolated  there- 
from.^^ 

Ash.  Analyses^^  of  the  male  fern  rhizome  have  shown  the 
ash  to  contain  the  basic  elements,  K,  Na,  Ca,.  Mg,  Al  and  Fe 
combined   with    the   acid  radicles  CI',  SO4'',  PO/",  SiOg''  and 


"'EhaLTd,  Ann.  Inst.  Pasteur  (1899),  13,  p.  456.  The  more  recent  work 
of  Willstaetter  and  his  pupils  on  the  chlorophylls  isolated  from  more  than 
200  different  plants  belonging  to  numerous  families  indicates  that  mag- 
Tiesium  is  a  constant  consituent  of  the  molecule,  which  is  considered  by 
them  to  be  a  methyl  phytyl  ester  of  the  tricarboxylic  acid,  chlorophyllin, 
'C3iH29N^Mg(COOH)3.  Viewed  in  this  light,  the  above  formulae  for  the 
aspidiophylls  are  erroneous  in  that  they  contain  no  magnesium  and  express 
molecular  weights  which  are  much  too  high.  Ann.  d.  Chem.  (1908),  358, 
p.  267;  Ibid.    (1910),  378,  p.  1. 

2»  Kruse  has  observed  that  the  rhizomes  collected  in  April  and  October 
:have  a  more  intense  green  color  than  those  gathered  in  July.  Arch.  d. 
Pharm.    (1876),  209,  p.   24. 

»Batso,  Trommsdorff's  n.  Journ.  d.  Pharm.  (1827),  14,  p.  294;  Peschier 
Ibid.  (1828),  17,  p.  5  and  Bock,  Arch.  d.  Pharm.  (ISBi),  115,  p.  266,  report 
the  presence  of  a  stearin-like  substance  in  the  ethereal  extract. 

Caesar  and  Loretz  have  observed  that  rhizomes  rich  in  wax  yield  an 
-ethereal  extract  which  is  not  fluid  at  the  ordinary  temperature.  GecJiaefts 
Ber.   (1897),  p.  62. 

30  In  the  light  of  our  present  knowledge  concerning  the  chemistry  of  male 
fern,  fllix  tannic  acid  Is  not  considered  to  be  a  constituent  of  the  oleoresin 
when  prepared  with  ether.  As  its  presence  in  the  latter  has  been  reported 
1)y  early  investigators,  the  above  description  has  been  included  here.  See 
-analysis  by  Bock,  Arch.  d.  Pharm.     1851,  115,  p.  266. 

"Malin,  Ann.  d.  Chem.  (1867),  115,  p.  276;  Wollenweber,  Arch.  d.  Pharm. 
<1906),   244,   p.    480. 

3' Wollenweber,  1.  c. 

»3Bock,  Arch.  d.  Pharm.  (1851),  115,  p.  257;  Spies,  Jahresb.  d.  Pharm. 
<1860),  20,  p.  15. 


gg  DU  MEZ— THE  GALENICAL  OLEORESINS 

CO3''.  Hell  and  Company^*  report  the  presence  of  0.0144  per 
cent,  of  copper.  Sp'ies,  however,  was  unable  to  detect  the  presence 
of  either  copper  or  manganese. 

The  ash  content  of  the  dried  rhizomes  varies,  about  2.0  to 
3.0  per  cent  being  the  usual  amount  obtained.^^ 

Constituents  of  Therapeutic  Importance 

The  value  of  the  oleoresin  of  aspidium  as  a  teniafuge  has 
at  various  times  been  attributed  to  either  its  filix  acid^  or  vola- 
tile oiP  content.  Comparatively  recent  pharmacological  in-^ 
vestigation,  ^  however,  has  shown  that  the  property  of  expell- 
ing the  tape  worm  is  not  due  to  a  single  constituent,  but  is 
shared  by  a  number  of  the  acid-like  components,  namely:  filix 
acid,  flavaspidic  acid,  albaspidin,  aspidinol,  flavaspidinin  and 
filmaron.  Of  these  substances,  filmaron  is  the  most  active  and 
is  stated  by  Jacquet*  and  others  to  be  the  constituent  of  most 
importance  therapeutically. 

The  diminution  in  the  therapeutic  activity  of  the  oleoresin 
on  ageing  has  been  found  to  be  due  to  the  breaking  down  of 
some  of  these  constituents  into  compounds  which  are  inert  or 
less  active  as  teniafuges.  Of  the  decomposition  products  tested 
by  Straub,  phloroglucin,  filicin  acid  and  butyric  acid  were 
found  to  be  non-toxic  when  administered  to  frogs.^  Filix  acid 
on  the  other  hand  was  found  to  be  toxic.  Its  value  as  a 
teniafuge  is,  however,  doubtful.* 

Physical  Properties 

Color:  The  color  of  the  oleoresin  varies  to  a  considerable 
extent  depending  principally  on  the  condition  of  the  drug  from 
which  it  is  prepared.  It  is  described  by  various  writers  as 
being  yellowish-green,    green,    dark  green   or   greenish-brown. 


34Pharm.  Post  (1894),  27,  p.  168;  Journ.  de  Pharm.  et  de  Chim.,  139, 
p.  493. 

^  Bock  gives  the  ash  content  of  the  air  dried  rhizomes  as  2.13  per  cent., 
Kruse  as  1.90  to  2.2  and  Spies  as  2.74.  For  the  exsicated  rhizomes,  the  latter 
obtained  3.19  per  cent. 

iPoulsson,  Arch.  f.  Exp.  Path.  u.  Pharmak.   (1891),  29,  p.  9. 

a  Robert,  Therap.   Monatsch.    (1893),   p.   136. 

8  Straub,  Arch.  f.  Exp.  Path.  u.  Pharmak.   (1902),  48,  pp.  1-47. 

*  Therap.   Monatsh.    (1904),   18,   p.    391. 

»Z.  c. 

•Boehm,  Arch.  f.  Exp.  Path.  u.  Pharmak.    (1897),   38,  p.  35. 


OLEORESIN  OF  ASPIDIUM  8T 

When  prepared  from  the  freshly  dried  and  powdered  rhizomes 
gathered  in  the  autumn/  it  usually  has  an  olive-green  color 
when  spread  out  in  a  thin  layer  on  a  white  porcelain  surface. 
A  brownish-green  color  is  an  indication  of  the  use  of  old  de- 
teriorated drug^  in  its  preparation,  whereas,  a  deep  green  color 
suggests  adulteration  with  salts  of  copper  or  chlorophyll.^ 

The  nature  of  the  solvent  employed  in  extracting  the  drug  is 
also  stated  to  have  an  influence  on  the  color  of  the  prepara- 
tion, the  use  of  ether  (specific  gravity  0.720)  yielding  an  oleo- 
resin  of  a  green  color,  whereas,  the  color  is  brownish-green 
when  ether  (specific  gravity  0.728)  is  employed.* 

Odor:  The  odor  of  the  oleoresin  is  peculiar,  like  that  of 
male  fern. 

Taste:  The  preparation  has  a  bitter,  nauseous,  subacrid 
taste. 

Consistence:  The  oleoresin  when  freshly  prepared  is  homo- 
geneous and  is  of  about  the  same  degree  of  fiuidity  as  castor 
oil.  It  is  variously  stated  as  being  of  the  consistence  of  syrup,, 
fresh  honey  or  an  oily  extract. 

Solubility:  The  oleore'sin  when  prepared  with  ether  forms 
clear  or  slightly  cloudy  solutions  with  acetone,  ether,  chloro- 
form and  carbon  disulphide.^  It  is  partially  soluble  in  carbon: 
tetrachloride,  benzene,  methyl  alcohol,  ethyl  alcohol  (95  per 
cent.),  glacial  acetic  acid  and  petroleum  ether.  The  degree  to 
which  it  is  soluble  in  the  last  three  solvents  mentioned  ha» 
been  made  the  basis  of  tests  for  the  detection  of  adulteration 
with  castor  oil. 

According  to  Hill  (1913),  not  less  than  8  volumes  of  the 
oleoresin  should  be  soluble  in  10  volumes  of  petroleum  ether, 
a  lesser  degree  of  solubility  indicating  adulteration.    Jehn  and 


*  The  oleoresin  prepared  from  rhizomes  gathered  in  October  is  stated  by 
Kruse  (1876)  to  have  a  more  intense  green  color  than  that  prepared  fronn 
rhizomes  gathered  in  July. 

Caesar  and  Loretz  in  their  Berichte  for  1913  state  the  condition  of  the 
season  in  which  the  rhizomes  are  harvested  has  an  influence  on  their  color, 
which  becomes  evident  in  the  oleoresin,  e.  g.  the  oleoresin,  when  prepared 
from  the  rhizomes  gathered  in  a  dry  season,  is  often  very  dark  green  in  color. 

'Buchner  (1826)  found  that  when  the  drug  was  kept  in  an  open  container 
for  more  than  a  year  a  brown  instead  of  a  green  colored  oleoresin  was  ob- 
tained. 

^Wepen  and  Lueders   (1892),  Beckurts  and  Peters    (1893)    and  others. 

*  Bellingrodt.   (1898). 

•This  statement  holds  good  only  for  the  freshly  prepared  oleoresin  ancJ 
does  not  apply  when  the  same  contains  deposited  material. 


88 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Crato^  state  that  the  presence  of  castor  oil  is  indicated  when 
more  than  50  per  cent,  of  the  oleoresin  is  soluble  in  95  per  cent, 
alcohol.  Solubility  tests  made  in  the  laboratory  with  glacial 
acetic  acid  have  shown  that  not  over  10  per  cent,  by  volume 
of  the  oleoresin  is  soluble  in  the  latter,  a  greater  degree  of 
solubility  indicating  adulteration  with  castor  oil. 

Specific  gravity:  Observations  made  in  the  laboratory  show 
that  the  specific  gravity  should  be  above  1.000  when  determined 
at  25  °C.  This  is  in  keeping  with  the  findings  of  Parry  (1911) 
and  Hill  (1913),  respectively,  even  though  their  determinations 
were  made  at  15° C.  It  is  also  the  standard  given  in  the  latei 
edition  of  the  British  Pharmacopoeia.  A  specific  gravity  of 
less  than  1.000  usually  indicates  adulteration  with  castor  oil 
or  a  preparation  naturally  low  in  filicin  content.  It  may,  how- 
ever, be  due  to  the  addition  of  chlorophyll  as  pointed  out  by 
Hill,  or  to  the  presence  of  unevaporated  solvent.  These  de- 
tails, together  with  the  effect  produced  by  the  use  of  different 
solvents  in  the  extraction  of  the  drug  are  brought  out  in  the 
following  tables: 


Table  IJi. — Specific  gravities  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity 

1 

1910... 
1916... 

DuMez&Netzel 

At25''C 
1  166 

2 

Acetone 

1  052 

3 

••             '♦       

Ether  

1  012 

4 

.4                                l(                                               •       • 

Petrol    ether 

0  995 

1 

DuMez 

1  048 

2 

Ether 

1  000 

1 

••  :::::::::::::::::::::: 

Acetone 

1.009  (2) 
0.997  (») 

2 

Ether 

^  Kommentar  zum  Arzneibuch  ftier  das  deutsche  Reich   (1901),  p.  258. 

2  Same  as  2  and  3  after  having  stood  in  the  laboratory  for  6  years.  Both 
contained  a  heavy  deposit  which  was  not  mixed  with  the  liquid  portion  when 
the   specific   gravity   was  redetermined.. 


OLEORESIN  OF  ASPimUM 


89 


Table  14. — Specific  gravities  of  commercial  samples. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
g-ravity 

1 

1911 
1912 

1913 
1913 

1913 

1915 
1916 

Parry 

Notffiven 

At  15°  C 
0.973    (1) 

2 

0.973    (1) 

3 

" 

" 

0.974    (') 

4 

" 

" 

0.975    (1) 

5 

" 

'• 

0.975    (») 

6 

•' 

>i 

0.988    (') 

1 

2 

Southall  Bros.  &  Barclay. 
Bohrisch 

"           

0.9745  (") 
0.0800  (i> 

3 

4 

"           

1.0148 
1.0200 

5 

•  ' 

1.0205 

6 

" 

1.0231 

1 

Temp.  ( ?) 
0.9836(3) 

2 

0.9842  (*> 

3 

" 

"             

0.9888  (») 

4 

" 

»' 

1.0109 

1 

DuMez 

Manila.  P.I 

At  25°  C 
0.977    (') 

2 

0.985    (i> 

3 

" 

United  States .............. 

0.9889  (i> 

4 

'* 

1.001 

5 

" 

Germany 

1.003 

6 

<■' 

1.003   (») 

7 

„         

UUnited  States 

1.008    {") 

8 

1.008 

1 

Harrison  &  Self 

Germany 

At  15°  C 
0.987    (♦> 

2 

V 

0.997 

3 

«» 

1.015 

4 

»• 

" 

1.020 

5 

'« 

«• 

1.029 

6 

" 

" 

1.029 

1 

Hill  

Europe 

0.9829  (3> 

2 

0.9850 

3 

'» 

»' 

0.9921 

4 

" 

1. 

0.9944 

5 

" 

" 

0.9980  c^y 

6 

»» 

'» 

0.9980  (1) 

7 

" 

0.9985  (1) 

8 

" 

1.000 

9 

«• 

•' 

1.000 

10 

'« 

»' 

2.0006  (»> 

11 

" 

" 

1.0036 

12 

" 

»« 

1.0045 

13 

" 

•' 

1.0065 

14 

»• 

" 

1.0075 

15    . .     . . 

" 

Rngrland 

1.0090 

16 

.4 

1.0109 

17 

1« 

1  0179 

18 

•' 

J.  0190 

19 

•' 

•' 

1.0227 

20 

" 

England 

1.0233 

21 

" 

Europe 

1.0235 

22 

•» 

1.0240 

23 

" 

•' 

1.0249 

1 

Southall  Bros.  &  Barclay. 
DuMez 

Not  srlven 

1.025 

2 

1.025 

1 

" 

0  9985 

2 

" 

1.0110 

8 

»« 

1.021 

4 

" 

1.023 

5 

»» 

1.030 

1 

Sauibb  &  Sons 

At25°C 
0.9808  O 

2 

Lilly  &Co 

0.9947  (') 

3     . 

" 

Parlte  Davis  &  Co 

1  0103 

4 

"         

Steams  &  Co 

1  0379  (') 

^  Adulterated  with  castor  oil. 

*  Contained  added  chorophyll. 
'  Low  in  crude  fllicin  content. 

*  Referred  to  as  suspicious. 

*  Contained  ether. 


90 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Refractive  index:  A  refractive  index  of  not  less  than  1.490 
at  40° C  is  required  for  this  oleoresin  by  the  late  edition  of  the 
British  Pharmacopoeia.  This  is  in  accordance  with  the  observa- 
tions of  Hill  (1913).  The  statement  by  Parry  (1911),  that 
the  refractive  index  should  not  be  below  1.500  when  deter- 
mined at  20  °C  is  confirmed  by  the  results  which  were  obtained 
by  Harrison  and  Self  (1913),  and  is  more  in  conformity  with 
the  observations  made  in  this  laboratory  at  25 °C.  When  the 
oleoresin  is  properly  prepared,  ether  being  the  menstruum  used, 
the  refractive  index  appears  to  vary  directly  as  the  crude  filicin 
content.  A  low  refractive  index,  therefore,  indicates  a  pre- 
paration naturally  low  in  filicin  content.  With  respeet  to  the 
commercial  oleoresins,  however,  a  low  refractive  index  may  also 
result  from  adulteration  with  castor  oil  or  chlorophyll,  or  may 
be  due  to  the  presence  of  unevaporated  solvent  as  is  shown  in 
the  tables  which  follow: 

Table  15.— Refractive  indices  of  laboratory  preparations. 


Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 


1913 


DuMez 

Harrison  &  Self. 


1916 


DuMez. 


Ether 

At  25°  G 
1.500 

At20°C 
1  4995 

1  5018 

1  5036 

"     

1.5088 
1.5088 
1.5102 
1  5120 

1.5122 

1.5126 

1  5145 

1.5157 

Acetone 

1  500^ 

Ether 

1.498' 

1  These  figures   represent   the   refractive    indices   of   oleoresins   which   had 
stood  in  the  laboratory  for  six  years. 


OLEORESIN  OF  ASPIDIUM 


91 


Table  16 — Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1 

1011 

1912 
1913 

1915 
1916 

Evans  Sons.Lescher  &Webb 
Parry 

Not  stated 

At  15°  C 
1.484(3) 

2 

1.485  (») 

3 

4 

..         

1.501 
1.501 

1 

.. 

At  20°  C 
1.484(1) 

2 

" 

1  484(1) 

3 



1.487  (') 

4 

»• 

1  488  (') 

5 

" 

'•                     

1.4885  (  ) 

6 

•» 

1  493(1) 

1-16 

Evans  Sons,Le8cher&Webb 
Sou  thai!  Bros.  &  Barclay  . 

DuMez 

,4 

At  15°  C 
1.507  to 

«• 

1.509 

1 

.. 

At  20°  C 
1.4830(1) 

2 

•' 

1.4840  (1) 

3 

1.5040 

4 

" 

1.5055 

5 

»• 

1.5065 

€ 

»• 

1.5210(?) 

1 

England  ....                  . 

At  25°  C 
1  484(1) 

2 

1  485  (1) 

3 

" 

Manila,  P.  I  . 

1.489 

4 

'• 

United  States 

1  490 

5 

•' 

1.490 

^ 

1.492 

7 

■* 

England 

1.493 

8 

'• 

Germany 

1  494 

1 

Harrison  &  Self 

At  20°  C 
1.4910 (») 

2 

1  4944 

3 

"                          *  * 

•  ' 

1.4984 

4 

•• 

'« 

1.5055 

5 

..                           •••• 

" 

1.5080 

f 

'• 

•• 

1  5084 

1 

Hill 

Europe 

At  40°  C 
1,4823  (1) 

2 

1.4869(1) 

3 

'• 

1  4874(1) 

4 

»* 

" 

1.4880 

5 

'« 

1.4909 

6 

" 

1.4915  (') 

7 

«« 

1.4920 

8 

England 

1.4922 

9 

Europe 

1.4925 

10 

1.4935 

11 

•• 

1.4940 

12 

•« 

1.4945 

13 

England 

1.4960 

14 

1.4965 

15 

1.4980 

16 

1.4985 

17 

»• 

1.4988 

18 

" 

1  4990 

19 

'» 

1.5006 

20 

•  •                          

" 

1.5025 

21 

" 

1.5036 

1  7 

Evans  SonsXescher  &Webb 

Southall  Bros.  &  Barclay  . 
Southall  Bros.  &  Barclay  . 

DuMez 

Not  stated 

At  15°  C 
1  500  to  1.510 

8 

1.495  (•) 

9 

•• 

1.497(3) 
1.499 (S) 
At  2,5»  C 
1.4975 

10 

1 

"     

2 

" 

1.5115 

1 

'• 

1.4976 

2 

•• 

1.4983 

3 

•« 

1.5000 

4 

•• 

1.5001 

5 

«» 

1.5020 

1 

Stearns  &  Co 

At  25°  C 
1.4953  (*) 

2 

Lilly&Co 

1.4988 (*) 

3 

•' 

Squibb  &  Sons 

1.4993 (*) 

4 

" 

Parke,  Davis  &  Co 

1.4998 

1  Samples  adulterated  with  castor  oil. 

»  Samples  contained  added  chlorophyll. 

*  Samples  are  referred  to  as  being  suspicious. 


92 


DU  MBZ— THE  GALENICAL.  OL.EORESINS 


Chemical  Properties. 

Loss  in  weight  on  heating:  Hill  (1913)  stated  that  the  oleo- 
resin  when  heated  at  100 °C  should  not  lose  more  than  6  per 
cent,  of  its  weight,  a  greater  loss  indicating  the  presence  of 
unevaporated  solvent.  The  statement  is  confirmed  by  other 
data  of  this  nature  reported  in  the  literature  as  well  as  by 
the  results  obtained  in  the  laboratory  as  is  shown  in  the  tables 
which  follow: 

Table  17 — Laboratory  preparations — Loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent 

of  loss  on 

heating: 

1 

1887 
1904 
1916 

Kremel 

Alcohol. 

At  100^  C 
17  40 

2 

Ether 

0  70 

] 

Dieterich 

4  51 

1  . 

DuMez 

Acetone 

At  lio" 
2  51C 

2 

Ether 

2  37 

OLEORESIN  OF  ASPIDIUM 


93 


Table  18 — .  Commercial  oleoresins — Loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent. 

of  loss  on 

heatinff 

1 

1891 
1893 

1894 

1895 
1896 
1897 

1901 
1903 

1904 

1905 

1913 

•• 

1914 
1916 

Dieterich 

Germany 

At  1()0°  C 
2.70 

1 

1.15 

2 

" 

1.60 

3        

•' 

1.75 

1 

'• 

1.90 

2 

•♦ 

2  32 

^ 

'• 

3  65 

1      

4» 

1.75    ■ 

1 

" 

1.62 

1      

" 

4.52 

2 

•• 

4  72 

1 

"                       *        * 

5.23 

1 

•« 

5  52 

2       

..                       " 

7.38 

1 

t< 

2.96 

2 

.' 

3.09 

1 

•• 

5.06 

2 

" 

7.51 

Hill 

Europe 

2  43 

2 

2.44 

3 

'• 

Eng'land 

2.57 

4 

•• 

Europe 

2.69 

^ 

" 

3.55 

R 

•• 

•« 

3.63 

7 

«' 

»» 

3  65 

}j 

It     

'• 

4.23 

9 

»• 

4  40 

10 

..        • 

4.57 

11 

'♦ 

4.64 

12 

»» 

4.84 

13 

•• 

England 

5  03 

14 

..     • 

5.22 

15 

•» 

6.500 

16 

•' 

6.52  (>) 

17 

»• 

•« 

6  60(1) 

18 

" 

'• 

6.68(1) 

1 

Unke 

Brtickner.  Lampe  &  C5o 

Caesar  &  Loretz 

At  l(X)tol05°C 
3.20 

2     ..  . 

3.25 

3 

•• 

Merck&Co 

6.85 

1 

DuMez 

Parke,  Davis  &  Co 

At  110°  C 
1.75 

2 

Stearns  &  Co 

2.03 

3 

•• 

Lilly&  Co 

6.01 

4 

41                              •                          •••      • 

Squibb  &  Sons 

7.18(1) 

(')  Unevaporated  solvent  (ether)  was  present. 


AsJi  Content:  The  results  of  this  nature  reported  in  the  lit- 
erature, as  well  as  those  obtaiined  in  the  laboratory,  indicate 
that  the  ash  content  of  the  oleoresin,  when  prepared  with  ether, 
seldom  exceeds  0.50  per  cent,  which  is  the  standard  given  in  the 
Belgian  and  Spanish  pharmacopoeias.  With  respect  to  the 
^commercial  samples  examined  in  the  laboratory,  the  high  ash 
content  obtained  was  due  to  the  presence  of  copper,  evidently 
a  result  of  the  use  of  copper  utensils  in  the  manufacture  of  these 
preparations.     The  results  of  the  determinations  made  in  the 


94 


DU  MEZ— THH  GALENICAL  OLEORESINS 


laboratory  and  those  reported  in  the  literature  are  given  in  the 
tables  which  follow : 


Table  19. — A»li  contents  of  laboratory  preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent 
of  ash. 

1 

1904 
1916 

Dieterich 

Ether 

0  36 

1 

DuMez : 

0.26 

2 

0  31 

Table  20 — Ash  contents  of  commercial  oleoresins. 


Sample 

No. 

Date 

Observer 

Source 

Per  cent 
of  ash 

Fereign  con- 
stituents 

1 

1891 
1893 

1894 

1895 
1896 
1897 

1901 
1903 

1904 
1905 
1914 

1916 

Dieterich 



\\        

;;    ::::■.::: 

Llnke ............ 

Germany  

0.40 

0.45 

0.50 

0.50 

0.42 

0.50 

0.55 

0.50 

0.45 

0.43 

0.52 

0.32 

0.27 

0.30 

0.39 

0.36 

0.83 

0.26 

0.46 

0.34 

0.41 

0.52 

0.52 

0.58 

0.54(1) 

0.80 

0.82 

1 

2 

«' 

3 

1 

2       .  ... 

3 

1 

1 

1      

2 

1 

1        .     .. 

2 

3         .... 

1 

2  

" 

1 

" 

2 

»• 

1 

Brueckner,  Lampe  &  Co  . . 
Caesar  &  Loretz.    .        .... 

Copper 

2 

3         .... 

"      

Riedel 

•' 

4 

Merck&Co 

Lilly  «&  Co 

1 

DuMez 

Copper 

2 

Squibb  &  Sons 

8  

" 

Parke,  Davis  &  Co 

•' 

4  

•' 

Stearns  &  Co 

»' 

(*)    Contained  unevaporated  solvent — ether. 

Acid  number:  The  acid  numbers  82.2  and  82.7  were  ob- 
tained for  the  oleoresins  prepared  in  the  laboratory.  Inas- 
much, however,  as  these  preparations  were  made  six  years 
previous  to  the  time  when  the  determinations  were  made,  it  is 
thought  that  the  value  of  this  constant  would  be  somewhat 
lower  for  the  oleoresin  when  freshly  prepared.  This  state- 
ment is  based  on  the  assumption  that  the  acidity  of  the  prep- 
aration will  increase  on  standing  due  to  the  partial  hydrolysis- 
of  the  glycerides  of  the  fatty  acids  and  to  the  breaking  down 
of  the  complex  substances  constituting  the  so-called  crude  filioin. 


OLEORESIN  OF  ASPIDIUM 


95 


In  the  case  of  the  commercial  samples,  the  acid  numbers  were 
found  to  vary  as  a  rule  in  the  same  direction  as  the  filicin 
content.  It  would  appear,  therefore,  that  the  value  obtained 
for  this  constant  might  serve  as  a  check  on  the  latter  determina- 
tion. The  results  obtained  in  the  determination  of  the  acid 
numbers  of  the  preparations  examined  in  the  laboratory  and 
those  reported  by  Kremel  follow: 


Table  21.— Acid  numbers  of  laboratory  preparations. 

Sample 
No. 

Date 

Observer 

Solvent 

Acid 
number 

1 

1887 
1916 

Kr^mel 

Alcohol 

23 

Ether 

50  to  70 

1 

DuMez 

82.7(1) 

2 

Acetone..  

82  2(1) 

(1)  These  preparations  were   6   years  old  when   the  acid   number  was   de- 
termined. 


Table  22 Acid  numbers  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Acid 
Number 

1 

1916 

Du  Mez 

Ptearns  &  Co 

50  2 

2 

Squibb  &  Sons 

65.90 

n 

•• 

Lilly&Co  

72  9 

4 

•  » 

Parkp.  Davis  Ar  Cn 

87.8 

(*)  Contained  ether. 


Saponification  value:  Determinations  made  by  Parry  in  1911 
lead  him  to  state  that  the  saponification  value  of  this  prepara- 
tion should  not  be  lower  than  230,  corresponding  to  a  crude 
filicin  content  of  not  less  than  22  per  cent.  The  values  obtained 
for  this  constant  in  the  laboratory  and  those  reported  by  Har- 
rison and  Self  agree,  as  a  rule  with  this  statement,  when  the 
minimum  filicin  content  is  taken  as  20  per  cent.  A  value  of 
less  than  230  in  the  case  of  commercial  samples  has  been  shown 
to  be  due  in  general  to  adulteration  with  castor  oil.  In  a  few 
instances,  however,  it  is  to  be  attributed  to  the  presence  of 
unevap orated  solvent,  or  to  a  low  filicin  content  due  to  the  use 
of  a  poor  quality  of  drug  in  the  manufacture  of  the  oleoresin. 


96 


DU  MEZ— THE  GALENICAL  OLEORESINS 


The  relatively  high  values  obtained  in  the  laboratory  for  the 
old  preparations  low  in  filicin  content  (16.0  and  16.27  per  cent, 
respectively)  is  very  likely  due  to  the  effect  caused  by  the 
hydrolysis  of  the  constituents  of  high  molecular  weight  with 
the  formation  of  acids  of  comparatively  low  molecular  weight.^ 
The  saponification  values  found  for  the  preparations  examined 
in  the  laboratory  as  well  as  those  reported  in  the  literature  are 
given  in  the  tables  which  follow: 


Table  23  — Saponification  values  of  laboratory  preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Saponifica- 
tion value 

1887 
1911 
1913 

1916 

Ether 

116  to  165 

1-20 

Parry 

van  to  250 

DuMez 

208.8 

Ether 

229  3 

Harrison  &  Self 

225.0 

227.0 

•' 

" 

236.5 

"           

248.0 

" 

248.9 

•• 

251  5 

" 

" 

252.0 

" 

254.5 

'» 

•• 

255  0 

10 

•• 

259.0 

11 

" 

>>                        "  *  * 

259  0 

DuMez 

245.2  (^) 

2 

Ether 

246  4  (0 

(*)  Old  preparations  low  in  filicin  content 


»See  under  "Chemistry  of  the  drug  and  oleroesin/ 


OLEORESIN  OF  ASPIDIUM 


97 


Table  24 — Saponification  values  of  commercial  oleoresins. 


Sample 
No. 

Date. 

Observer. 

Source. 

Saponifica- 
tion value 

1 

1904 
1911 

1912 
1913 

1915 
1916 

Dieterich 

204.4 

2. 

234  2 

1 

Evans  Sons,  Lescher  & 
Webb 

195.2  (1) 
220  4 

2 

5 

'« 

248.8 

1 

Parry 

" 

197.0  (» 

2 

200  0  (0 

3 

" 

'• 

207.0  (0 
208.0  (0 
210.0  (" 

4 

" 

;;     

5 

«'                 

6 

" 

" 

221.0  (1) 

195.1  (0 
204.6  (1) 
235.4 

1 

Southall  Bros.  &  Barclay. 
DuMez 

*' 

2 

\\ • 

3 

4 

«» 

241.0 

5 

•' 

256.3 

6 

258  2 

1 

England 

195.7  (0 
200.3  (3) 
202  4  0) 

2    ... 

Manila,P.I 

3 

" 

4 

>. 

United  States 

206.7  (2) 
208.7  (I) 

5 

" 

England 

% 

Germany 

214.6  (3) 
225.5 

7.. 

% 

-i 

United  States 

240  5 

1 

Harrison  &  Self 

205.0  (3) 
213.0 

2  ..     .. 

3 

.i            •••• 

" 

218  0 

4  . 

»' 

*» 

223  0 

5 



'« 

225.0 

6 

" 

" 

237.0 

1 

Southall  Bros.  &  Barclay. 
DuMez 

Not  given 

225.1 

2 

263.1 

" 

206.5 

3 

'• 

236.0 

3 

"         

250.0 

4 

253.1 

5 

•<■ 

254  6 

1 

Stearns  <fe  Co 

190.0  (2) 

2 

Lilly  &  Co 

211.4  (") 

3. 

" 

Sauibb  &  Sons 

233  2  («) 

4 

" 

Parke,  Davis  &  Co 

249.1 

1  Adulterated  with  castor  oil. 

2  Lovsr  in  crude  fllicin  content. 
2  Referred  to  as  suspicious. 

*  Contained  ether. 


Iodine  value:  Observations  made  in  the  laboratory  indicate 
that  the  oleoresin  should  have  an  iodine  value  of  not  less  than 
99,  corresponding  to  at  least  20  per  cent,  of  crude  filicin.  Pre- 
parations giving  a  lower  value  than  this  were  found  to  be  low 
in  crude  filicin  content  due  to  adulteration  with  castor  oil  or 
to  the  presence  of  unevaporated  solvent.  On  the  other  hand, 
it  was  observed  that  a  high  iodine  value  does  not  always  signify 
a  high  filicin  content,  e.  g.  iodine  values  of  106.3  and  108.1 
were  obtained  for  preparations  containing  only  16.0  and  16.27 
per   cent,   of  crude  filicin,   respectively.     As  the  latter  were 


98 


DU  MEZ— THE  GALENICAL  OLEORESINS 


old  and  contained  deposited  material  equal  to  nearly  one-half 
of  their  bulk,  the  high  iodine  values  obtained  for  the  super- 
natent  liquid  portions  were  very  likely  due  to  the  concentra- 
tion of  the  compounds  of  a  lesser  degree  of  saturation  (glycer- 
ides  of  the  unsaturated  fatty  acids)  as  a  result  of  the  decom- 
position and  deposition  of  the  more  highly  saturated  com- 
pounds (crude  filicin).  The  results  obtained  in  the  determina- 
tion of  this  constant  are  shown  in  the  following  tables : 

Table  25. — Iodine  values  of  laboratory  'preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Iodine  valu» 

1 

1911 
1913 
1913 
1916 
1916 

Evans  Sons,  Lescher  &  Webb 

DuMez 

Ether 

101  8 

1 

Acetone               , 

95  3 

2 

Ether 

99.8 

1 

" 

Acetone  . 

106  3  (1) 

2 

Ether 

108.1  (I) 

These  preparations  were  six  years  old  when  examined. 

Table  26. — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Iodine 
value 

I 

1804 
1911 

1913 
1916 

Dieterich 

100.6 

2 

84.2 

1 

Evans  Sons, Lescher  &  Webb 
DuMez 

Not  given 

89.2vO 

z       .... 

92. 3(') 

3 

95.9 

4         

t.       .1 

99.1 

\ 

England 

85.8('> 

2         

Manila.?.  I 

England 

87.2 (») 

3 

». 

89.4  (1) 

4        

*» 

United  States 

94.4 

5 

it 

Germany 

97.1 

g 

" 

98.3  (') 

7 

" 

Germany 

100.2 

8 

'' 

United  States 

101.5 

1 

n 

Squibb  &  Sons 

95. 3(')  • 

2 

»' 

Stearns  &  Co 

97.7  C') 

3         .... 

'« 

Lillv&  Co 

98.2(») 

4 

" 

Parlie,  Davis  «fe  Co 

103.2 

1  Adulterated  with  castor  oil. 

2  Low  in  crude  fllicin  content. 
'  Contained  ether. 


Other  Properties 

The  oleoresin,  when  freshly  prepared,  is  homogeneous,  but 
upon  standing,  a  deposit  is  formed  therein  as  a  result  of  the 
breaking  down  of  some  of  its  constituents.     The  precipitated 


OL.EORESIN  OF  ASPIDIUM  99 

material  has  been  identified  by  Boehm^  as  crystalline  filix  acid 
and  a  wax-like  substance.  Kraft,^  in  a  later  investigation,  con- 
firmed the  findings  of  Boehm  insofar  as  they  concerned  the 
presence  of  filix  acid.  The  wax-like  material,  however,  he 
found  to  be  composed  of  a  number  of  substances,  decomposi- 
tion products  of  the  therapeutically  active  constituents,  which 
he  designated  as  filixnigrin.  As  the  deposit  has  been  found  to 
be  active^  in  the  expulsion  of  tapeworm,  although  in  a  much 
lesser  degree  than  the  oleoresin  proper,  the  United  States  PJiar- 
macopocia  directs  that  it  be  mixed  with  the  liquid  portion  be- 
fore dispensing. 

Special  Qualitative  Tests 

A  number  of  the  European  pharmacopoeias  prescribe  tests 
for  the  determination  of  the  quality  of  this  preparation.  These 
tests  are  of  two  kinds,  namely,  those  which  have  for  their  object 
the  establishment  of  the  presence  of  the  constituents  of  thera- 
peutic value,  i.  e.  the  substances  of  an  acid  character  known 
collectively  as  crude  filicin,  and  those  which  serve  to  identify 
starch  when  present.  The  former  are  based  on  the  fact  that 
the  above  mentioned  constituents  of  an  acid  character  may  be 
precipitated  directly  by  means  of  certain  solvents,  or  from 
alkaline  solutions  by  means  of  acids.  The  following  are  the 
official  tests  of  this  nature : 

Tests  for  Filicin. 

Austrian  Pharmacopoeia  (1906) :  Upon  adding  an  excess  of  petroleum 
ether  to  the  oleoresin  dissolved  in  a  small  quantity  of  ethyl  ether,  a  white 
precipitate  should  be  produced. 

'  Netherlands  Pharmacopceia  (1905) :  If  0.025  gram  of  the  oleoresin  dis- 
solved in  2  cubic  centimeters  of  ether  be  shaken  with  5  cubic  centimeters 
of  a  saturated  barium  hydroxide  solution  and  5  cubic  centimeters  of  water, 
the  aqueous  portion,  when  separated  and  filtered,  should  give  a  floccu- 
lent  precipitate  on  being  acidified  with  hydrochloric  acid. 

Hungarian  Pharmacopoeia  (1909) :  If  0.25  gram  of  the  extract  be  dis- 
solved  in  2  cubic  centimeters  of  ether  and  shaken  with  10  cubic  centi- 
meters of  lime  water,  the  aqueous  portion  filtered  and  acidified  with  hydro- 
chloric acid,  a  copious  white  precipitate  should  be  formed. 


^Arch.  f.  exp.  Path.  u.  Pharmak.   (1897),  38,  p.  85. 
'Kraft    (1902). 

'Renter,   Pharm.   Ztg.    (1891),  36.  p.   245;   Straub,  Arch.  f.   exp    Path    u 
Pharmak.  (1902),  48,  p.  1.  v.  .      . 


100  ^U  MEZ— THE  GALENICAL  OLEORBSINS 

The  application  of  these  tests  in  the  laboratory  has  shown 
that  they  are  of  practically  no  value  as  an  indication  of  the 
quality  of  the  oleoresin,  as  preparations  very  low  in  crude 
filicin  content  give  comparatively  heavy  precipitates  when 
treated  as  described  above.  Furthermore,  they  do  not  serve 
as  a  means  of  identification  as  oleoresins  prepared  from  the 
rhizomes  of  certain  other  species  of  fem^  behave  in  a  similar 
manner  when  subjected  to  these  conditions. 


Tests  for  Starch 

A  test  for  the  presence  of  starch  has  been  included  in  those 
pharmacopoeias  in  which  the  oleoresin  is  directed  to  be  pre- 
pared by  the  process  of  maceration,  namely,  the  German  and 
Japanese.  In  these  instances,  it  serves  as  a  means  of  distin- 
guishing between  preparations  which  have  been  filtered  as  of- 
ficially directed  and  those  which  have  been  merely  strained 
through  cloth  as  is  often  the  case.  A  similar  test  is  also  found 
in  the  pharmacopoeias  of  those  countries  (Hungary,  Spain  and 
Switzerland)  in  which  this  preparation  is  frequently  made  by 
maceration,  although  the  official  process  is  that  of  percolation. 
The  test  as  officially  recognized  in  the  different  countries  is 
identical  with  that  described  in  the  German  Pharmacopoeia. 
It  is  as  follows: 

The  oleoresin,  when  diluted  by  shaking  with  glycerin,  should  not 
show  the  presence  of  starch  grains  under  the  microscope. 

Experience  in  the  application  of  this  test  to  the  preparations 
examined  in  the  laboratory  has  shown  that  it  is  unsatisfac- 
tory when  carried  out  as  described  above.  The  fault  lies  in 
the  fact  that  the  glycerin  cannot  be  thoroughly  mixed  with 
the  oleoresin  by  shaking.  If  mixing  is  effected  by  trituration 
in  a  mortar,  the  results  are  better,  although  there  is  consider- 
able danger  in  rupturing  the  starch  grains  by  this  procedure. 

In  addition  to  the  foregoing,  special  tests  have  been  pro- 
posed for  the  detection  of  adulterants  when  present.  They 
are  as  follows: 


*Bee  under  "Drug  used.  Its  collection,  preservation,  etc' 


OLEORESIN  OF  ASPIDIUM  IQl 


Tests  for  the  Presence  of  the  Oleoresin  of  Dryopteris  Spinulosa. 

Hausmann  found  that  the  male  fern  of  commerce  frequently- 
contained  large  quantities  of  the  rhizomes  of  Dryopteris  spinv^ 
losa  Kunze.  He  therefore  devised  a  test  for  the  detection  of  the 
use  of  the  latter  in  the  preparation  of  the  oleoresin.  It  is  based 
on  the  fact  that  the  rhizomes  of  Dryopteris  spinulosa  Kunze 
contain  aspidin,  whereas  those  of  the  official  species,  Dryopteris 
Filixmas  Schott  do  not. 

Eausmann's  Method  (1899):  Dissolve  a  small  amount  of  crude  filicin* 
in  as  small  a  quantity  of  absolute  ether  as  possible  and  set  the  solution 
aside  in  a  desiccator.  If  aspidin  is  present,  the  thick  solution  will  form 
a  crystalline  brine  in  a  few  hours,  when  the  needle-like  crystals  of  the 
former  can  easily  be  identified  under  the  microscope.  If  aspidin  is  not 
present,  the  solution  undergoes  no  change  even  on  long  standing  except 
to   deposit  a  granular  substance. 

Tests  for  the  Presence  of  Castor  OH 

The  tests  for  the  presence  of  castor  oil  are  based  on  the 
solubility  of  the  oleoresin  in  various  solvents  and  are  discussed 
under  the  heading,  **  Solubility. ' ' 

Tests  for  the  Presence  of  Salts  of  Copper 

The  tests  for  the  presence  of  salts  of  copper  involve  an  ex- 
amination of  the  ash  of  the  oleoresin  and  are  discussed  under 
the  general  treatment  of  the  subject,  **Ash  content/' 

Special  Quantitative  Tests. 

A  great  deal  of  work  has  been  done  with  reference  to  the 
evaluation  of  this  preparation,  and  as  a  result,  a  number  of 
methods  for  the  quantitative  estimation  of  the  constituents  of 
therapeutic  importance  has  been  devised.  The  chemical  meth- 
ods may  be  conveniently  divided  into  two  groups,  the  one  includ- 
ing those  methods  which  have  for  their  object  the  quantitative 
determination  of  the  filix  acid;  and  the  other  comprising  the 
methods  in  which  the  quantity  of  the  total  constituents  of  an 
acid  character  is  determined. 


*See  under  "Special  quantitative  methods". 


2Q2  DU  MEZ— THE  GALENICAL.  OLEORESINS  ■    ■     -     " 

Methods  for  the  Determination  of  Filix  Acid. 

As  the  oleoresin  was  originally  thought  to  owe  its  teniafuge 
properties  to  its  filix  acid  content,  the  determination  of  this 
constituent  naturally  received  consideration  first.  The  nature 
of  the  methods  devised  for  its  estimation  and  their  subsequent 
development  is  illustrated  in  the  descriptions  which  follow : 

Method  of  Kremel  (1887) :  Place  a  weighed  quantity  (about  10  grains) 
of  the  oleoresin  in  a  flask  and  macerate  it  successively  with  several  portions 
of  petroleum  ether  when  the  greater  part  will  be  dissolved  leaving  the 
filix  acid  as  an  insoluble  residue.  Collect  the  latter  on  a  fiilter  and  wash 
with  more  petroleum  ether.  Then  dissolve  it  while  on  the  filter  in  hot 
alcohol,  remove  the  latter  by  evaporation  and  again  wash  with  petroleum 
ether  to  remove  the  last  traces  of  fat.       Finally  dry  and  weigh. 

Method  of  Bocchi  (1896) :  *  Dissolve  1  to  2  grams  of  the  oleoresin  in  a 
small  quantity  of  ether,  place  the  solution  in  a  separatory  funnel  and 
shake  it  with  successive  portions  of  lime  water  until  the  shakings  become 
colorless  and  remain  clear  on  the  addition  of  acetic  or  hydrochloric  acids. 
Filter  the  united  lime  water  solutions  into  a  separatory  funnel  and  acidify 
with  hydrochloric  acid  when  a  dirty  yellow  precipitate  will  form.  Dis- 
solve the  latter  by  shaking  with  carbon  disulphide  added  in  successive 
portions,  unite  the  shakings,  filter  and  remove  the  solvent  by  evaporation 
on  a  water  bath.     Dry  and  weigh  the  residue  which  is  pure  fili;x  acid. 

Method  of  Kraft  (1896):  Add  a  solution  composed  of  2  grams  of 
potassium  carbonate,  40  grams  of  water  and  60  grams  of  alcohol  (95  per 
cent.)  to  5  grams  of  the  oleoresin  in  a  suitable  flask  and  shake  for  15 
minutes.  Filter  83  grams  of  this  liquid  into  a  separatory  tunnel,  add  9 
grams  of  dilute  hydrochloric  acid,  50  grams  of  ether  and  35  grams  of 
water  and  shake  vigorously.  After  the  mixture  has  separated  draw  off 
the  lower  hydro-alcoholie  liquid  and  repeat  the  shaking,  using  35  grams 
more  of  water.  Separate  the  latter  and  run  the  remaining  ethereal  so- 
lution into  a  tared  Erlenmeyer  flask  of  100  cubic  centimeters  capacity. 
Distill  off  the  greater  part  of  the  ether  and  evaporate  the  remainder  down 
to  about  2  grams.  Dissolve  the  dried  mass  in  1.5  grams  of  amyl  alcohol 
and  precipitate  the  filix  acid  by  the  addition  of  30  cubic  centimeters  of 
methyl  alcohol  (5  cubic  centimeters  added  at  once  and  the  remainder  drop 
by  drop.)  Allow  the  precipitate  and  supernatant  liquid  to  stand  over 
night  in  a  cool  place,  then  collect  the  former  on  a  tared  filter  and  wash 
it  with  15  cubic  centimeters  of  methyl  alcohol  (use  3  portions  of  5  cubic 
centimeters.)  Finally,  dry  the  precipitate  at  a  temperature  between  60° 
and  70 "C  and  weigh.  The  weight  obtained  will  represent  the  filix  acid 
contained  in  4  grams  of  the  oleoresin. 


^The  procedure   as  outlined   above   really  grives  the  amount  of  total  acid 
substances  (crude  filicin)   present,  but  is  described  here  as  it  was  proposed 
by  its  originator  as  a  method  for  the  determination  of  the  filix  acid  content 


OLEORESIN  OF  ASPIDIUM  ^Q3 

Original  Method  of  Fromme  (1896):  Dissolve  1.5  to  2  grams  of  the 
«leoresin  in  2  grams  of  ether,  and  thoroughly  mix  the  solution  in  a  porce- 
lain dish  (diameter  8  to  10  centimeters)  with  3  grams  of  calcined  mag- 
nesia (or  8  grams  of  burned  lime.)  Allow  the  ether  to  evaporate  com- 
pletely and  triturate  the  remaining  dry  pulverent  mass  with  water,  added 
gradually  until  a  thin  brine  is  formed.  Set  the  mixture  aside  until  the 
magnesia  has  settled,  then  decant  the  supernatant  aqueous  portion  on  a 
•dry  filter.  Continue  to  repeat  this  operation,  using  fresh  portions  of 
water,  until  the  filtrate  no  longer  gives  a  precipitate  when  acidified  with 
hydrochloric  acid.  Place  the  combined  filtrates  (usual  weight  200  to  250 
grams)  in  a  separatory  funnel,  acidify  with  hydrochloric  acid  and  shake 
out  the  precipitate  with  carbon  disulphide  added  in  successive  portions 
(20,  10  and  10  cubic  centimeters.)  Filter  the  united  carbon  disulphide 
shakings  into  a  round-bottom  flask  of  100  cubic  centimeters  capacity  ^nd 
evaporate  to  dryness  on  a  water  bath.  Dissolve  the  crude  filix  acid  ob- 
tained in  this  manner  in  10  drops  of  amyl  alcohol,  using  a  gentle  heat 
if  necessary,  then  add  10  cubic  centimeters  of  methyl  alcohol  (added  drop 
by  drop  at  the  beginning  and  later  rapidly.)  Set  the  liquid  containing 
the  crystals  aside  in  a  cool  place  for  12  hours,  then  collect  the  latter  on  a 
tared  filter,  and,  after  washing  with  several  5  cubic  eentimener  portions 
of  methyl  alcohol,  dry  at  a  temperature  between  60°  and  70  °C  and  weigh. 

Improved  Method  of  Fromme  (1897):  Place  5  grams  of  the  oleoresin, 
30  grams  of  ether  and  100  grams  of  a  solution  of  barium  hydroxide  (1  per 
cent.)  in  a  200  cubic  centimeter  flask  and  shake  for  5  minutes.  Then  run 
the  mixture  into  a  separatory  funnel,  and,  after  allowing  it  to  stand  for  10 
to  15  minutes,  run  off  into  another  separatory  funnel  86  grams  (cor- 
responding to  4  grams  of  the  oleoresin)  of  the  lower  aqueous  layer. 
Acidify  by  the  addition  of  hydrochloric  acid  (25  to  30  drops)  and  shake 
out  with  ether  (in  25,  15,  10  and  10  cubic  centimeter  portions.)  Filter 
the  combined  ether  washings  into  a  100  cubic  centimeter  flask  and  evapor- 
ate to  dryness  on  a  water  bath.  Dissolve  the  residue  in  1  cubic  centimeter 
of  amyl  alcohol  by  heating  over  a  free  flame  and  precipitate  the  pure  filix 
acid  with  30  cubic  centimeters  of  methyl  alcohol  (added  drop  by  drop 
until  a  permanent  precipitate  is  produced,  and  the  remainder  at  once.) 
After  the  liquid  has  stood  quietly  in  a  cool  place  for  10  to  12  hours, 
collect  the  precipitate  on  a  tared  filter,  wash  with  methyl  alcohol  (two  5 
cubic  centimeter  portions,)  press  the  filter  between  porous  plates,  dry  at 
an  initial  temperature  of  40  °C  and  finally  at  80 °C,  and  weigh. 

Stoder's  Method  (1901):  Dissolve  5  grams  of  the  oleoresin  in  20  cubic 
centimeters  of  ether,  add  100  cubic  centimeters  of  a  freshly  prepared  so- 
lution of  barium  hydroxide  (2  per  cent.)  and  shake  the  mixture  fre- 
quently during  1  hour.  After  allowing  the  mixture  to  stand  quietly  for 
a  short  time,  separate  the  lower  aqueous  layer  by  filtration.  Collect 
86  cubic  centimeters  of  this  portion  (corresponding  to  4  grams  of  the 
oleoresin)  in  a  separatory  funnel  and  acidify  with  10  cubic  centimeters  of 
dilute  hydrochloric  acid.  Shake  out  the  resulting  precipitate  with  three 
portions  of  ether  (40,  30  and  20  cubic  centimeters)  added  successively, 
unite  the  shakings  and  remove  the  solvent  by  distillation.       Dissolve  the 


104 


DU  MEZ— THE  GALENICAL  OLEORESINS 


residue  in  1  cubic  centimeter  of  amyl  alcohol,  and,  after  the  solution  has 
stood  in  a  cool  place  for  48  hours,  add  15  cubic  centimeters  of  methyl 
alcohol.  After  standing  for  24  hours  more,  collect  the  precipitated  filii 
acid  on  a  filter,  wash  with  5  cubic  centimeters  of  methyl  alcohol,  dry  on 
a   water   bath    and   weigh. 

It  will  be  noticed  that  the  preceding  methods,  with  the  ex- 
ception of  the  one  devised  by  Kremel,  are  very  similar  in  gen- 
eral outline,  practically  the  only  difference  being  found  in  the 
procedure  by  which  the  crude  filix  acid  is  directed  to  be  purified. 
This  difference  is  of  special  importance,  however,  as  the  weight 
of  the  product  finally  obtained  will  naturally  vary  with  the  de- 
gree to  which  purification  has  been  effected,  and  this  in  turn 
will  cause  the  computed  percentage  to  vary,  as  is  shown  in  the 
following  table : 

Table  'il .—  Variation  in  filix,  acid  content  due  to  the  difference  in  the  meth 
ods  employed  in  its  determination. 


Observer 

Per  cent,  of  filix  acid  by  the  metliod  of 

Date 

Bocchi 

Kraft 

Fromme 
(Original) 

Fromme 
(Improved) 

1887 

Gehe  &  Co 

Madsen 

13.24  to  S0.35 

3.28  to  11.32 

13.07 

6.58 

6.00 

1897 

12.10 

1897 

5.85 

1898 

Plzak 

6.48 

5.20 

The  above  table  shows  further  that  the  filix  acid  is  obtained 
in  the  state  of  greatest  purity  when  the  improved  method  of 
Fromme  is  employed.  And  this  method  was  usually  given 
preference  in  the  valuation  of  the  oleoresin  until  it  was  dis- 
covered that  the  teniafuge  properties  were  not  due  to  the  filix 
acid,  alone,  but  were  to  be  attributed  in  part  to  the  presence  of 
a  number  of  other  substances  as  well,  compounds  resembling 
acids  to  a  certain  extent  in  their  chemical  behavior. 


Methods  for  tJie  determination  of  the  Crude  Filicin. 

With  the  above  mentioned  advance  in  our  knowledge  con- 
cerning the  therapeutic  constituents  of  this  preparation,  the 
methods  for  the  determination  of  the  filix  acid  lost  their  value 
and  have  since  been  superceded  by  those  which  have  for  their 


OLEORESIN  OP  ASFIDIUM  105 

object  the  determination  of  the  quantity  of  total  active  constit- 
uents (crude  filicin)  present.  The  methods  which  have  been 
proposed  for  this  purpose  are  as  follows: 

Method  of  Bulle  (1867)  :"■  Add  a  liberal  amount  of  water  to  a  weighed 
portion  of  the  oleoresin  contained  in  a  suitable  flask  and  heat  on  a  water 
bath  at  40°  to  50  °C.  Add  sufficient  ammonia  water  to  produce  a  strong 
odor  of  the  same  after  vigorously  shaking.  Allow  the  mixture  to  stand 
in  cold  water  for  3  or  4  hours  and  add  1/5  to  i/4  of  its  volume  of  a  sat- 
urated solution  of  salt,  then  filter.  Wash  the  flask  and  filter  with  the 
salt  solution,  diluted  with  6  parts  water,  until  the  filtrate  no  longer  gives 
a  precipitate  with  hydrochloric  acid.  Add  dilute  hydrochloric  acid  to  the 
filtrate  until  precipitation  is  complete,  collect  the  precipitate  on  a  filter, 
wash  and  dry  over  sulphuric  acid  until  of  constant  weight. 

Method  of  Daccomo  and  Sccocianti  (1896) :  ^  Dissolve  1  to  3  grams  of 
the  oleoresin  in  a  small  quantity  of  ether  and  shake  the  solution  for  % 
hour  with  an  equal  volume  of  an  aqueous  copper  acetate  solution.  Allow 
the  mixture  to  stand  and  separate,  decant  the  ethereal  liquid  and  collect 
the  precipitate  on  a  tared  filter.  Wash  it  successively  with  water,  alco- 
hol and  ether,  then  heat  at  100°C  until  of  constant  weight.  When  dry 
111.55  parts  of  the  precipitate  represent  100  parts, of  filix  acid. 

Method  of  Schmidt  (1903)  :  ^  Place  5  grams  of  the  oleoresin  in  a  mortar 
and  convert  it  to  a  coarse  powder  by  triturating  it  with  a  sufficient  quantity 
of  calcined  magnesia.  Then  add  250  cubic  centimeters  of  water  and  thor- 
oughly mix.  After  the  magnesia  has  settled,  decant  the  aqueous  portion 
on  a  filter.  Repeat  this  operation  twice  using  150  cubic  centimeters  of 
water  each  time.  Transfer  the  combined  filtrate  to  a  separatory  funnel 
and  add  hydrochloric  acid  in  sufficient  quantity  to  produce  complete  pre- 
cipitation. Shake  out  the  precipitate  with  ether,  specific  gravity  0.720  to 
0.722,  added  in  successive  portions  (100,  50  and  30  cubic  centimeters.) 
After  filtering  the  ethereal  shakings,  remove  the  solvent  by  distillation 
and  dry  the  residue  at  100*C. 

Method  of  Fromme  (1905) :  *  Dissolve  5  grams  of  the  extract  in  30 
grams  of  ether,  add  100  grams  of  a  saturated  solution  (3  per  cent.)  of 
barium  hydroxide,  and  shake  the  mixture  vigorously  during  several  minutes. 
Transfer  to  a  separator,  and  run  86  grams  (4  grams  of  the  extract)  of  the 
lower  equeous  layer  into  a  flask  of  200  cubic  centimeters  capacity.  Add 
2  grams  of  hydrochloric  acid  (25  per  cent.)  and  shake  out  with  3  portions 
of  ether,  25,  15,  and  10  cubic  centimeters.  Separate  the  ether,  and  filter 
each   portion   successively    through    the    same    plain    double    filter    into    an 


1  Cited  by  Doesterbehn   (1898). 

2  This  procedure  was  proposed  as  a  method  for  the  estimation  of  the 
illix  acid.  As  its  nature  and  the  results  obtained  In  its  application  show  that 
it  is  in  reality  a  method  for  determining  the  total  constituents  of  an  acid 
•character,  It  has  been  included  here. 

•The  method  proposed  by  Goris  and  VoisIn  (1913)  is  almost  identical 
with  the  above,  the  only  difference  being-  that  2  to  3  grams  of  the  oleoresin 
are  taken  instead  of  5  grams  as  directed  by  Schmidt, 

*This  is  the  method  (but  slightly  modified)  which  is  official  in  the  British, 
Finnish  and  Swiss  pharmacopceias. 


106 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Erlenmeyer  flask  of  200  cubic  centimeters  capacity  which  has  been  pre- 
viously weighed.  Wash  the  filter  with  10  cubic  centimeters  more  of  ether^ 
and  finally  distill  off  the  ether  and  dry  the  residue  at  100 °C.  Weigh  after 
allowing  it  to  stand  in  a  desiccator  for  half  an  hour.  The  weight  multi- 
plied by  25  will  give  the  percentage  of  crude  filicin  in  the  sample. 


The  striking  similarity  in  the  above  methods  is  quite  ap- 
parent and  needs  no  special  mention.  Attention,  however,  is 
invited  to  the  principal  point  of  difference,  namely,  the  reagent 
employed  for  the  purpose  of  rendering  the  constituents  to  be 
determined  soluble  in  water.  In  the  methods  under  considera- 
tion, ammonia  water,  magnesium  oxide  and  barium  hydroxide 
have  been  made  use  of.  As  the  amount  of  crude  filicin  ob- 
tained has  been  shown  to  depend  to  a  considerable  extent  upon 
which  one  of  these  reagents  is  employed,  the  difference  in  the 
results  reported  in  the  literature  in  this  connection  is  readily 
accounted  for.  The  importance  of  this  factor  is  clearly  brought 
out  in  the  following  data  obtained  by  Hill : 

Table  28 — Influence   of  different  alkalies  on    the  percentage  of  crude 
filicin  obtained. 


Alkali 

K2CO3 

1  per  cent 
KOH 

6 per  cent. 
KOH 

Mfir(OH)2) 

Ca(0H)2 

Ba(0H)2 

Per  cent,  of  crude 
filicin 

37.6 

37.9 

38.8 

1S,6 

20.0 

21.6 

These  results  would  appear  to  indicate  that  potassium  hy- 
droxide is  the  most  efficient  reagent  for  effecting  a  soluble  com- 
bination of  the  constituents  comprising  the  so-called  crude 
filicin.  The  data,  however,  are  misleading  in  that  the  strong- 
alkali  combines  with  other  material  therapeutically  inert,  and 
thereby  causes  the  results  to  be  high.  While  there  is  no  in- 
formation of  a  physiological  nature  at  hand  to  substantiate  the 
statement  that  barium  hydroxide  is  the  best  reagent  for  this 
purpose,  it  is  nevertheless,  thought  to  be  the  most  satisfactory 
from  a  chemical  stand  point  at  least.  The  method  of  Fromme^ 
in  which  the  latter  is  directed  to  be  used,  was,  therefore,  em- 
ployed in  the  evaluation  of  the  oleoresins  examined  in  the 
laboratory.  The  results  obtained  in  these  analyses,  together 
with  those  reported  by  other  workers  are  given  in  the  table 
which  follows: 


OLEORESIN  OF  ASPIDIUM: 


107 


Table  29. — Crude  filicin  content  of  laboratory  samples  of  the  oleoresin 
determined  hy  Fromme's  method. 


Sample 
No. 

Date 

Observer 

Solvent 

Crude 
filicin 

1 

1898 

1899 
1913 

1914 
1916 

Bellincrnflt 

EtbPT- 

Percent. 
18.20 

2 

. 

18.96 

3 

• 

19  82 

4 

20.38 

5 

' 

20.87 

6 

* 

t 

21.76 

7 

' 

21.85 

8 ^. 

• 

24  32 

1 

Caesa 

Bohn 
DuMe 

Harri 

Linke 
DuMe 

31.44» 

2 

27. 48^^ 

1 

sch 

18.22 

1 

»z 

Ac 
Etl 

Ac( 
Etl 

Btone 

13.79 

2 

20.37 

1 

son  &  Self 

19.30 

2 

* 

19.70 

3....  . 

21.50 

S::::::::: 

" 

' 

21.90 

3 

" 

24.10 

6 

•' 

24.20 

7 

»» 

24  50 

8 

" 

24.70 

9 

•' 

26.50 

10.... 

27.70 

11 

»' 

28.0 

1 

19.30 

2 

z." 

16. 00^ 

2 

ler 

16.27  ' 

1  Ether,  specific  gravity  0.720. 

=»  Ether,  specific  gravity  0.728. 

'  Oleoresins  which  were  prepared  in  1910  and  had  deteriorated.  Exam- 
ined shortly  after  being  prepared,  the  ethereal  oleoresin  showed  a  crude 
filicin  content  of  26.35  per  cent. 

From  the  foregoing,  it  is  apparent  that  the  crued  filicin 
content  is  influenced^  by  the  age  of  the  oleoresin  as  well  as  by 
the  solvent  which  has  been  employed  in  its  preparation.  In  the 
case  of  acetone,  the  low  results  obtained  are  not  due  to  the  in- 
complete extraction  of  the  constituents  to  be  determined,  as 
might  be  inferred,  but  rather  to  the  relatively  large  amount  of 
total  extractive  matter  obtained.  It  will  be  noticed  that  when 
the  oleoresin  is  fresh  and  ether  is  the  solvent  which  has  been 
used  in  its  preparation,  the  crude  filicin  content  is  usually 
above  20  per  cent.  This  is  in  accordance  with  the  require- 
ments of  the  British  Pharmacopoeia  and  is  thought  to  be  a  more 
reasonable  standard  than  that  adpoted  by  the  Swiss,  or  the 
Finnish  pharmacopoeias.  The  former  requires  a  filicin  content 
of  26  to  28  per  cent,  while  the  latter  specifies  a  minimum  con- 
tent of  26  per  cent.  This  statement  is  further  supported  by 
the  results  obtained  in  the  examination  of  commercial  samples 
as  is  shown  in  the  following  compilation  of  such  data : 


*For  the  effect  of  the  condition  of  the  rhizomes  used  on  the  crude  filicin 
content,  see  under  "Drui^  used,  its  collection,  preservation,  etc.'/ 


108 


DU  MEZ — THE  GALENICAL  OLEORESINS 


Table  30. — Crude  filicin  content  of  commercial  samples  of  the  oleoresin 
determined  by  Fromme's  method. 


Sample 
No. 

Date: 

Observer 

Source 

Crude  fllicin 

1 

1901 

1903 
1911 

1912 
1913 

1913 

C. 

lesar  &  Loretz 

Prepared  by  the  firm 

England    

Per  cent. 
21.40 

2 

3 

26.15 
27.37 

4 

5 

28.17 
30.00 

6 

30.12 

7 

8 

30.80 
30.92 

1 

27.08 

2 

4i                                            4» 

28.22 

3 

28.78 

4 

14                                            (> 

29.39 

5 

6 

30.05 
36  60 

1 

Evans  Snns.  T^ftsr>her  & 

26.30 

2 

Webb.  ^^ 

28.00 

P 
E 

irry 

" 

8.40  (1) 

2 

8.60  (1) 

3 

" 

" 

8.80  (1) 

4 

" 

44 

9,00  (1) 

5 

" 

" 

9.20  (1) 

6 

" 

'4 

10.80  (1) 

Ito  16.. 

vans  Sons.    T^fisr'.her  & 

22.90  to  26.30 

1 "... 

2 

Webb. 
South  all  Bros.  &  Barclay 

:;      

6.09  0) 
7.16  (0 

3 

4 



26.04 
28.76 

1 

B 
D 

E 

ohrlsch  

Germany           

14.85 

2 

15.42 

3 

" 

16.00 

4 

uMez 

" 

24.00 

1 

Enjrland 

8.79 

2 

United  States     

14.36 

3 

4' 

Germany 

England        .   .     .      

16.55 

4 

44 

17.51  (») 

5 

" 

20.32 

6 

44 

United  States 

20.77 

Ito  7 

8 

9 

vans  Sons,  Lescher   & 
Webb. 

Not  given 

21.3  to  25.30 

15.60  0) 
19.60  (0 

10.... 

" 

4.                           4. 

19.70  (0 

G 
H 

H 

oris  &  Voisin 

Germany               

13.61  to  19.00 

7.13  to  24.00 

France 

20  60  to  22.13 

1 

13.70 

2.. 

19.10 

3 

4 

'•           "       

" 

21.20 
24.80 

5 

44                                  44 

44 

25.80 

6 

44                              4. 

44 

28.10  (IS 
11.60  },{ 
13.20  )A 
14.10  ^  ^ 

1 

ill 

2 

3 

" 

4 

Not  given 

18.10 

5 

18.92 

6 

4.                           44 

19.30 

7.. 

(4                           44 

20.22 

8  

44 

20.67 

9 

44                        44 

21.57 

10 

44                           44 

21.60 

11  

44 

22.00 

12 

[',                           i.            

22.65 

13 

23.10 

OLEORESIN  OF  ASPIDIUM 


109 


Table  30. —Continued. 


Sample 
No. 


14 

1913 

15 

16 

" 

17 

'* 

18 

" 

19 

" 

20 

" 

21 

" 

22 

" 

23 

*' 

1 

1914 

2 

3 

1 

"mh" 

2 

3 

'• 

4 

" 

5 

•' 

1916 

2 

3 

" 

4 

" 

Date 


Observer 


Hill. 


Linke 

Southall  Bros.  &  Barclay 


DuMez  . 


Source 


Not  given. 


Merck  &  Co 

Brueckner,  Lampe  &  Co. 

Caeser  &  Loretz  

Notgiven 


Stearns  &  Co 

Lilly  &  Co 

Squibb  &  Sons 

Parke,  Davis  &  Co. 


Crude  fllicin 


Percent. 

23,72 
23.75 
24.50 
24.55 
25.15 
25.27 
27.10 
27.82 
28.10 
29.75 
20.40 
21.67 
27.22 
20.40 
21.60 
24.20 
24.60 
27.70 
7.79  (2) 
17.57 
19.04 
22.66 


1  These  samples  were  adulterated  with  castor  oil. 

'Apparently    an   oleoresin   from   some    species   of    fern    other    than   Dry- 

opteris  Mix-mas. 

In  addition  to  the  information  gtiven  in  table  No.  29,  table 
No.  30  reveals  the  fact  that  a  low  filicin  content  in  the  com- 
mercial oleoresins  is  frequently  due  to  adulteration  with  castor 
oil. 


Physiological  Tests. 

In  view  of  the  difference  in  toxicity  of  the  various  constit- 
uents of  the  oleoresin  with  respect  to  the  tapeworm,  a  physio- 
logical method  for  the  evaluation  of  this  preparation  would  ap- 
pear to  be  desirable.  The  method  proposed  for  this  purpose 
by  Yagi  indicates  the  possibilities  along  this  line.  However, 
as  there  is  no  available  information  regarding  its  application, 
aside  from  that  given  by  the  originator,  no  statement  can  be 
made  concerning  its  practical  value.  A  description  of  the 
method  for  conducting  the  test  follows  : 

Method  of  Yagi  (1914):  After  thoroughly  drying  in  a  desiccator,  ac- 
curately weigh  1  gram  of  the  oleoresin  and  dissolve  it  in  25  cubic  centi- 
meters of  ether.  Bring  the  therapeutically  active  constituents  into 
aqueous  solution  by  shaking  the  ethereal  liquid  with  a  saturated  solution 
of  magnesium  hydroxide,  using  50  cubic  centimeters  of  the  latter  for  every 


110 


DU  MEZ— THE  GALENICAL  OLEORESINS 


cubic  centimeter  of  the  former.  Filter  and  divide  the  filtrate  into  several  parts. 
Prepare  solutions  of  different  dilution  from  these  parts  -  by  adding  a 
measured  amount  of  water  to  each.  Then  immerse  5  earthworms  in  each 
of  these  solutions  and  note  the  maximum  dilution  in  which  all  5  are  killed. 
For  computing  the  relative  value  of  the  preparation  compare  these  re- 
sults with  those  obtained  when  using  a  standard  solution  prepared  by  dis- 
solving a  weighed  amount  of  filix  acid,  filmaron  or  albaspidin  in  water  in 
the  same  manner  as  described  above  for  the  oleoresin.  In  the  case  of  these 
standard  solutions  the  limit  of  toxicity  is  given  as  follows:  filmaron,  3 
parts  in  1,000,000;  filix  acid  4  parts  in  1,000,000;  albaspidin  1  part  ia 
100,000. 

Adulterations 

The  efforts  which  have  been  made  in  recent  years  to  stand- 
ardize this  preparation  have  resulted  in  the  discovery  that  the 
commercial  article  is  very  frequently  adulterated,  the  latter 
being  accomplished  in  a  variety  of  ways. 

The  method  usually  resorted  to  by  unscrupulous  manufac- 
turers in  order  to  increase  their  profits  consists  of  diluting  the 
finished  product  with  some  comparatively  cheap  material. 
Castor  oiP  has  generally  been  used  for  this  purpose.  In  some 
cases,  the  oleoresin  is  prepared  from  deteriorated  brown  rhi- 
zomes and  made  to  assume  the  green  color  of  the  official  pre- 
paration by  the  addition  of  chlorophyll  or  salts  of  copper.^ 

Adulteration,  however,  is  not  limited  to  the  addition  of  for- 
eign materials  to  the  finished  product,  but  may  take  place  in 
the  drug  from  which  the  oleoresin  is  prepared.  The  forms  in 
which  the  drug  may  be  contaminated  are  conveniently  classed 
under  three  heads,  viz.:  (a)  the  substitution  of  old  deteriorated 
rhizomes  for  the  fresh  material,  (b)  the  admixture  of  chaff 
and  dead  stipe  bases  with  the  rhizomes,  and  (c)  the  admixture 
of  rhizomes  of  unofficial  species  of  fern  with  those  of  the 
official  species.  For  a  discussion  of  these  conditions,  see  under 
^'Drug  used,  its  collection,  preservation,  etc." 


^  Parry   (1911)  ;  Evans  Sons,  Lescher  and  Webb   (1911)  ;  and  others, 
^Weppen    and    Lueders    (1892);    Beckurts    and    Peters    (1893);    PendorfiC 

(1913)  ;  and  others. 
A  trace  of  copper  is  usually*  present  in  the  commercial  product  as  a  result 

of  the  use  of  copper  utensils  in  the  manufacture  of  the  preparation.      (See 

under  "Ash"). 


OLEORESIN  OF  CAPSICUM  HI 

OLEORBSIN  OF  CAPSICUM 

Sy7ionyms 

Aetherische  SpunishpfefferextraTct,  Nat.  Disp.  1884. 

Capsicum,''  Chem.  &  Drugg.  (1913),  82,  p.  470. 

Capsicol,  Vierteljahrschr.  f.  prakt.  Pharm.   (1873),  22,  p.  507. 

Ethereal  Extract  of  Capsicum,  Am.  Journ.  Pharm.  (1849),  21,  p,  134. 

Extractum  Capsici  aethereum,  Hirch,  Univ.  P.  Ii90'2,  No.  1905. 

Oleoresin  of  Bed  Pepper,  Stevens,  Pharm.  and  Disp.  (1909),  p.  255. 

Oleoresina  Capsici,  U.  S.  P.  1910. 

Oleoresine  de  Capsique,  U.  S.  Disp.  1907. 

SpanishpfefferextraTct,    Nat.   Disp.    1884. 

Spanishpfefer-Oelharz,  Nat.  Disp.  1884. 

History 

The  oleoresin  of  capsicum  appears  to  have  been  first  prepared 
by  Procter  in  1849,  and  it  was  through  his  efforts  that  it  was 
introduced  into  the  United  States  Pharmacopma  of  1860.  Up 
to  the  present  time,  no  such  preparation  appears  in  any  of  the 
foreign  pharmacopoeias.  A  similar  preparation  known  as  capsi- 
ein  has,  however,  been  in  use  in  Europe  since  1873.^ 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

The  drug  directed  to  be  used  by  the  present  edition  of  the 
United  States  PJiarmacopoeia  is  ''the  dried  ripe  fruits  of  Capsi- 
cum fructescens  Linne^  (Fam.  Solanaceae),  without  the  presence 
or  admixture  of  more  than  2  per  cent,  of  stents,  calyxes  or  other 
foreign  matter."  The  preceding  editions  of  the  Pharmacopoeia 
since  1880  have  specified  the  use  of  the  species  known  as  Capsi- 
cum fastigiatum  Blume.  The  change  is  evidently  due  to  the 
fact  that  the  leading  commercial  varieties  of  Cayenne  pepper 
are  at  the  present  time  being  received  from  Africa  and  Japan  and 


^For  other  uses  of  the  term  capsicin,  see  under  "Chemistry  of  capsicum 
and  its  oleoresin." 

=*  Buchheim  states  that  capsicin  (the  ethereal  extract  of  capsicum)  was 
being  prepared  and  sold  by  Merck  of  Darmstadt  in  1873.  Vierteljahrschr. 
f.  prakt.  Pharm.   (1873),   22,  p.  507. 

Capsicin,  as  found  on  the  market  in  England,  is  stated  to  be  indefinite  in 
that  it  may  be  an  alcoholic,  a  chloroformic,  an  ethereal  or  an  acetone  prep- 
aration.    Chem.  and  Drugg.    (1913),  82,  p.  470. 

3  This  is  also  the  species  recognized  by  the  French  Pharmacopoeia.  In  the 
other  European  pharmacopoeias,  in  which  this  drug  occurs,  it  is  usually  the 
the  larger  fruited  variety,  Capsicum  annum,  which  is  designated. 


112  ^^  MEZ— THE  GALENICAL.  OL.EORESINS 

belong   to   the  first  mentioned   species*   which   has   also  been 
known  as  Capsicum  haccatum  Veil. 

The  fruit  is  plucked  when  ripe,  exposed  to  the  sun  until  dried, 
and  then  usually  packed  in  suitable  shape  for  market.  It  should 
be  preserved  in  the  whole  condition  in  a  cool  place,^  and  prefer- 
ably in  a  closed  container  as  it  is  prone  to  become  rancid  owing 
to  the  large  amount  of  fatty  oil  which  it  contains. 

U.  S.  P.  Texts  and  Comments  Thereon. 

The  oleoresin  has  been  official  in  the  United  States  Phar- 
macopoeia  for  the  past  half  century  having  been  recognized  for 
the  first  time  in  the  edition  of  1860. 

1860 

Oleoresina  Capsici 
Oleoresin  of  Capsicum 
Take  of  Capsicum,*    in    fine  powder,'   distillation  on  a  water-bath,  eighteen 
twelve  troy-ounces;  fluid-ounces  of  ether,"  and  expose  the 

Ether '  a  sufficient  quantity.  residue,  in  a  capsule,     until     the  re- 

Put  the  capsicum  into  a  cylindrical  maining  ether  kas  evaporated.  "^ 
percolator,*  press  it  firmly,  and  grad-  Lastly,  remove,  by  straining,  the  fatty 
ually  pour  ether  upon  it  until  twenty-  matter  which  separates  on  standing,* 
four  fluid  ounces  of  filtered  liquid  and  keep  the  Oleoresin  in  a  well-stop- 
have  passed.'    Eecover  from  this,  by   pered  bottle." 

1870 

Oleoresina  Capsici 
Oleoresin  of  Capsicum 

Take  of  Capsicum,*  in  fine  powder,^  ounces  of  liquid  have  slowly  passed.* 
twelve  troyounces;  Eecover  the  greater  part  of  the  ether 
Ether  ^  a  sufficient  quantity.  by  distillation  on  a  water -bath,'  and 
Put  the  capsicum  into  a  cylindrical  expose  the  residue  in  a  capsule,  until 
percolator,  provided  with  a  stop-cock,  the  remaining  ether  has  evaporated.'^ 
and  arranged  with  cover  and  recep-  Lastly,  remove,  by  straining,  the  fatty 
taele  suitable  for  volatile  liquids,*  matter  which  separates  on  standing,* 
press  it  firmly,  and  gradually  pour  and  keep  the  Oleoresin  in  a  well-stop- 
ether  upon  it,  until  twenty-four  fluid  pered  bottle.*". 


*Tolman  and  Mitchell,  Bull.  163,  Bur.  of  Chem.   (1913),  p.  9. 
'Brown,  Bull.  150,  Kentucky  Agric.  Exp.  Sta.   (1910),  p.  131. 


OLEORESIN  OF  CAPSICUM  113 

1880 

Oleoresina  Capsici 

Oleoresin  of  Capsicum 

Capsicum/    in    No.    60    powder/    one   residue,  in  a  capsule,  until  the  remain- 

Hundred  parts  100   ing  ether   has  evaporated/       Lastly, 

Stronger  Ether,^  a  sufficient  quantity,  pour  off  the  liquid  portion,"  transfer 
Put  the  capsicum  into  a  cylindrical  the  remainder  to  a  strainer,  and,  when 
percolator,  provided  with  a  cover  and  the  separated  fatty  matter  (which  is 
receptacle  suitable  for  volatile  liquidflj*  to  be  rejected)  has  been  completely 
press  it  firmly,  and  gradually  pour  drained,  mix  all  the  liquid  portions  to- 
stronger  ether  upon  it,  until  one  hun-    gether." 

dred  and  fifty   (150)  parts  of  liquid       Keep  the  oleoresin  in  a  well  stop- 
have     slowly     passed.**       Kecover  the    ped  bottle." 

greater  part  of  the  ether  by  distilla-       Preparation.    Emplastrum  Capsici. 
tion  on  a  water-bath,"  and  expose  the 


1890 

Oleoresina  Capsici 

Oleoresin  of  Capsicum 

Capsicum,*  in  No.  60  powder,^  five  a  water-bath,"  and,  having  transferred 
hundred  grammes 500  Gm.  the  residue  to  a  capsule,  allow  the  re- 
Ether,^  a  sufficient  quantity.  maining  ether  to  evaporate  spontan- 
Put  the  capsicum  into  a  cylindrical  eously.^  Then  pour  off  the  liquid  por- 
glass  percolator,  provided  with  a  stop-  tion,  transfer  the  remainder  to  a 
cock,  and  arranged  with  cover  s^nd  strainer,  and,  when  the  separated  fatty 
receptacle  suitable  for  volatile  liquids,*  matter  (which  is  to  be  rejected)  has 
Press  the  drug  firmly,  and  percolate  been  completely  drained,  mix  the  li- 
slowly  with  ether,  added  in  successive  quid  portions  together.' 
portions,  until  the  drug  is  exhausted.'  Keep  the  oleoresin  in  a  well-stop- 
Eecover  the  greater  part  of  the  ether  pered  bottle.", 
from  the  percolate  by  distillation  on  Preparation:     Emplastrum  Capsici. 


114 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


1900 


Oleoresina  Capsici 
Oleoresin  of  Capsicum 


Capsicum/    in    No.    40    powder,'    -five 

hundred  grammes 500  Gm. 

Acetone/  a  sufficient  quantity. 

Introduce  the  capsicum  into  a  cylin- 
drical glass  percolator,  provided  with 
a  stop-cock,  and  arranged  with  a 
cover  and  a  receptacle  suitable  for 
volatile  liquids.*  Pack  the  powder 
firmly,  and  percolate  slowly  with  ace- 
tone, added  in  successive  portions, 
until  eight  hundred  cubic  centimeters 
of  percolate  have  been  obtained." 
Recover  the  greater  part  of  the  ace- 
tone   from   the   percolate   by   distilla- 


tion on  a  water-bath,*  and,  having 
transferred  the  residue  to  a  dish,  al- 
low the  remaining  acetone  to  evapor- 
ate spontaneously  in  a  w^arm  place.' 
Then  pour  off  the  liquid  portion,* 
transfer  the  remainder  to  a  glass  fun- 
nel provided  with  a  pledget  of  cotton, 
and  when  the  separated  fatty  matter 
(which  is  to  be  rejected)  has  been 
completely  drained,  mix  the  liquid 
portions  together.*  Keep  the  oleo- 
resin in  a  well-stoppered  bottle.^** 

Average      dose. — 0.030       Gm.  z=z  30 
milligrammes    (^   grain). 


1910 
Oleoresina  Capsici 
Oleoresin  of  Capsicum 
Oleores.  Capsic. 


Capsicum,^     in     No.     40  powder*  ^ive 

hundred  grammes 500  Gm. 

Ether,'  a  sufficient  quantity. 

Place  the  capsicum  in  a  cylindrical 
glass  percolator,  provided  with  a  stop- 
cock, and  arranged  with  a  cover  and 
a  receptacle  suitable  for  volatile  li- 
quids.* Pack  the  powder  firmly  and 
percolate  slowly  with  ether,  added  in 
successive  portions,  until  the  perco- 
late measures  eight  hundred  mils.^ 
Eecover  the  greater  part  of  the  ether 
from  the  percolate  by  distillation  on 
a  water-bath,«  and,  having  transferred 


the  residue  to  a  dish,  allow  the  re- 
maining ether  to  evaporate  spontan- 
eously in  a  warm  place.^  Then  pour 
off  the  liquid  portion,'  transfer  the 
remainder  to  a  glass  funnel  provided 
with  a  pledget  of  cotton,  and,  when 
the  separated  fatty  matter  (which  is 
to  be  rejected)  has  been  completely 
drained,  mix  the  liquid  portions  to- 
gether." Keep  the  oleoresin  in  a  well- 
stoppered  bottle." 

Preparation  —  Eplastrum      Capsici. 

Average  Dose. — Metric,  0.03  Gm. — 
Apothecaries,  %  grain. 


OLEORESIN  OF  CAPSICUM  115 

1)  For  a  description  of  the  drug,  see  pag  1017  under  ''Drug 
used,  its  collection,  preservation,  etc." 

2)  The  editions  of  the  Pharmacopoeia  previous  to  that  of  1900 
directed  that  the  drug  be  reduced  to  a  fine  powder  (No.  60) 
for  percolation.  As  a  No.  40  powder  has  been  found  to  be 
equally  satisfactory  for  this  purpose,  the  last  two  editions 
of  the  PharmacopcBia  have  specified  the  use  of  the  coarser 
powder. 

3)  Ether  is  the  solvent  which  is  directed  to  be  used  in  the  ex- 
traction of  the  drug  at  the  present  time.  Previous  editions  of 
the  Pharmacopoeia,  with  the  exception  of  that  1900,  also,  speci- 
fied the  use  of  ether  for  this  purpose.  The  use  of  acetone  as  di- 
rected by  the  Pharmacopoeia  of  1900  was  unsatisfactory  as  the 
large  amount  of  extractive  matter  obtained  caused  the  residue 
which  remained  upon  the  evaporation  of  the  solvent  to  assume  a 
semi-solid  gelatinous  form,  and  thus  increased  the  difficulty 
of  separating  the  liquid  portion. 

Among  the  other  solvents  which  have  received  considera- 
tion in  this  connection,  benzin  is  worthy  of  mention.  The  re- 
ports of  Maisch,  Trimble  and  Beringer,  respectively,  (see 
part  I,  pages  923  and  924)  indicate  that  it  is  a  good  solvent  for 
the  oleoresinous  constituents  of  capsicum  and  that  the  pro- 
duct obtained  is  equal  in  quality  to  that  yielded  by  ether. 
Experiments  conducted  in  the  laboratory  confirm  these  ob- 
servations. The  solvent  used  in  the  laboratory,  however,  was 
petroleum  ether,  boiling  temp,  45  to  50°  C,  as  the  composition 
of  ordinary  commercial  benzin  varies  to  a  considerable  extent. 

4)  The  Pharmacopoeia  of  1860  directed  that  the  extraction 
of  the  drug  be  carried  out  in  an  ordinary  glass  percolator.  As 
a  considerable  amount  of  solvent  was  lost  under  these  condi- 
tions, the  subsequent  editions  of  the  Pharmacopoeia  have 
specified  that  a  form  of  percolator  adapted  to  the  use  of  vola- 
tile liquids  be  employed  for  this  purpose.  For  a  description 
of  such  forms,  see  Part  I,  under  *' Apparatus  used.'' 

5.)  Of  interest  in  connection  with  the  preparation  of  this 
oleoresin  is  the  fact  that  the  pharmacopoeial  directions  con- 
cerning the  amount  of  percolate  to  be  collected  have  been 
changed  no  less  than  three  times.  The  first  change  appeared 
in  the  Pharmacopoeia  of  1880,  and  was  apparently  instituted 
for  economic  reasons  as  the  amount  of  percolate  directed  to 


116  DU  MEZ— THE  GALENICAL.  OLEOKBSINS 

be  collected  was  reduced  from  approximately  2  cubic  centi- 
meters for  each  gram  of  drug  used  (24  fluid  ounces  for  12  troy 
ounces  of  drug)  to  1.5  cubic  centimeters.  In  the  succeeding 
edition  of  the  Pharmacopoeia  (edition  of  1890),  the  second 
change  was  made,  the  directions  being  to  continue  percolation 
until  the  drug  is  exhausted.  The  third  change  occurs  in  the 
Pharmacopoeia  of  1900,  which  directs  that  1.6  cubic  centi- 
meters of  percolate  be  collected  for  each  gram  of  drug  taken. 

The  reason  for  making  the  second  change  does  not  become 
apparent  from  the  information  at  hand.  The  third  change^ 
however,  appears  to  have  been  instituted  primarily  for  the 
purpose  of  reducing  the  amount  of  solid  fats  (mainly  pal- 
mitin  and  stearin)  extracted  in  order  that  the  separation  of 
the  liquid  portion  constituting  the  oleoresin  might  be  ac- 
complished more  easily. 

In  commenting  further  upon  these  changes,  it  is  stated  that, 
in  the  preparation  of  the  oleoresin  in  the  laboratory,  no 
greater  difficulty  was  experienced  in  the  separation  of  the 
liquid  portion  when  the  amount  of  sold  fats  present  was  large 
than  when  the  quantity  present  was  relatively  small.  From 
this  standpoint,  therefore,  the  last  change  does  not  appear  to 
have  been  warranted.  For  economic  reasons,  however,  the 
change  was  desirable  since  at  least  twice  as  much  ether  was 
required  for  the  complete  exhaustion  of  the  drug  as  is  ordin- 
arily used  when  proceeding  according  to  the  directions  given 
in  the  last  edition  of  the  Pharmacopoeia. 

It  is  thought  that  the  present  pharmacopoeial  method  could 
be  still  further  improved  through  the  use  of  some  form  of  con- 
tinuous extraction  apparatus  for  exhausting  the  drug.  Not 
only  would  this  procedure  result  in  the  saving  of  a  large 
amount  of  solvent,  but  the  time  required  to  complete  the 
preparation  of  the  oleoresin  would  be  considerably  shortened. 

6)  The  Pharmacopoeia  of  1860  directed  that  only  %  of  the 
menstruum  contained  in  the  percolate  be  recovered  by  distil- 
lation on  a  water  bath.  In  all  of  the  subsequent  editions  the 
directions  are  to  recover  the  greater  part  of  the  solvent,  no 
specific  amount  being  mentioned.  In  this  connection,  it  may 
be  stated  that  the  preparation  will  not  be  injured  even  if  all 
of  the  solvent  is  recovered  under  the  above  conditions.  In 
case  this  is  done,  however,  it  is  necessary  to  use  ether  in  re- 


OLEORESIN  OF  CAPSICUM  ll7 

moving  the  thick  liquid  from  the  flask  so  that  no  particular 
advantage  is  gained  by  such  a  procedure. 

7)  In  all  editions  of  the  Pharmacopoeia  in  which  this  prepara- 
tion is  official,  it  is  directed  that  the  last  traces  of  solvent  be 
allowed  to  evaporate  spontaneously  at  room  temperature. 
Since  the  complete  removal  of  the  solvent  can  be  accomp- 
lished much  more  rapidly  by  heating  the  ethereal  liquid  on  a 
water  bath,  and  without  injury  to  the  finished  product,  it  is 
thought  that  such  a  procedure  would  be  a  desirable  improve- 
ment over  the  present  pharmacopoeial  method. 

8-9)  The  liquid  portion  constituting  the  oleoresin  is  directed 
to  be  separated  from  the  solid  fats,  which  precipitate  up- 
on the  removal  of  the  solvent,  by  decantation,  and  straining 
through  a  pledget  of  cotton.  Experience  has  shown  that  this 
may  be  accomplished  much  more  rapidly  and  satisfactorily  by 
the  aid  of  a  force  filter.  By  this  procedure  a  more  complete 
separation  can  be  effected  without  washing  the  residue  on  the 
filter  with  a  portion  of  the  solvent  as  has  been  suggested  by 
some  and  thus,  the  necessity  of  further  exposure  of  the  prep- 
aration to  the  air  is  done  away  with. 

With  further  reference  to  the  removal  of  the  solid  fats,  at- 
tention is  called  to  the  fact  that  the  degree  to  which  this  is  ac- 
complished depends  upon  the  temperature  at  which  the  oper- 
ation is  carried  out.  The  preparation  when  made  during  the 
summer  may  be  perfectly  homogeneous  at  the  time,  but  deposit 
fat  during  the  winter.  In  order  to  secure  a  more  uniform 
product,  it  is  therefore,  thought  that  the  Pharmacopoeia 
should  direct  that  the  mixture  be  chilled  to  a  definite  tempera- 
ture previous  to  the  separation  of  the  liquid  portion. 

10)  The  oleoresin  should  be  kept  in  well-stoppered  bottles  for 
the  same  reasons  as  are  given  in  the  comments  on  the  oleoresin 
of  aspidium.     See  page  979. 

Yield 

The  average  yield  of  oleoresin  is  usually  about  15  to  18  per 
cent,  when  ether  is  the  solvent  employed  in  exhausting  the 
drug.  It  is  about  the  same  when  alcohol,  acetone,  petroleum 
ether,  carbon  disulphide  or  chloroform  are  used.  In  this  con- 
nection, attention  is  called  to  the  fact  that  the  total  amount  of 


118  DU  MEZ— THE  GALENICAL  OLEORESINS 

extract  obtained  and  the  oleoresin  are  not  identical,  the  latter 
consisting  only  of  the  oily,  liquid  portion  of  the  former.  Thus, 
it  will  be  observed,  upon  examining  the  tables  which  follow,  that 
the  total  amount  of  extract  obtained  with  acetone  may  amount 
to  25  per  cent,  of  the  drug  operated  upon,  whereas,  the  yield 
of  oleoresin  is  only  about  18  per  cent.  The  factor  which  ap- 
pears to  influence  the  yield  to  the  greatest  extent  is  the  tem- 
perature at  which  the  preparation  is  completed.  This  is  due 
to  the  fact  that  the  oleoresin  is  saturated  with  solid  fats 
(principally  palmitin)  and,  that  these  will  be  precipitated  to 
a  greater  or  lesser  degree  depending  on  the  temperature  at 
which  the  preparation  is  finally  strained.  The  finished  pro- 
duct will,  therefore,  contain  a  relatively  small  amount  of  these 
fats,  and  the  yield  will  be  correspondingly  low  when  made  dur- 
ing the  cold  winter  months,  whereas,  the  opposite  will  be  the 
case  when  the  oleoresin  is  prepared  in  the  hot  months  of  sum- 
mer. The  following  tables  show  the  yield  of  oleoresin,  as  re- 
ported in  the  literature,  likewise,  that  obtained  in  the  labora- 
tory: 


OLEORESIN  0F  .CAPSICUM 


119 


Table  31. — Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  oleoresin  to 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1853 

Bakes  

Perct 
25.00 

Per  ct 

Per  ct 

Percent. 

888 

Trimble 

19.50 
17.32 

15.50 
17.40 
18.30 
18.40 
19.00 

15.81 
16.85 
21.31 
16.19 

15.67 
15.34 

j      Benzin 
1        18.15 
21.00 

25.00 

1892 

18.00 
25.00 

Yield  of   oleoresin   when  pre- 

1892 

Sherrard, 

28.00 

paied  b.v  the  U.  S.  P.  method. 
Total  yield  of  extract  on  com- 
plete exhaustion  of  the  drug. 

Alpers  

1896 

Oleoresin  from  which  deposited 

1898 

Wlnton,  Ogden  & 
Mitchell 

fat  had  been  removed. 
Total  ether  extract  from  "Chilli 

Southall  B10S.& 
Barclay 

Colorado." 
Total  ether  extract  from  Natal 

capsicum. 
Total  ether  extract  from  Ne- 

paul  capsicum. 
Total  ether  extract  from  Zan- 

1903 

zibar  capsicum. 
Capsicum  minimum  total  .yield 

Vanderkleed 

to  ether,  sp.  gv.  Q.717. 
Capsicum  annum  total  yield  to 

1905 

j     9olvent(?) 
19.40  to  23  90 

J      Benzin 
»        18.60 
\     Petrol 
<    Ether 
\        16.40 
\      Carbon 
X    disulDhlde 
1        16.70 
j  Chloroform 
(        17.50 

ether.sp.gr.  0.717. 
Reported  as  yield  of  oleoresin. 

1905 

Gerrard 

fAIco- 
Jhol 
1  (905t) 
126.40 

18.20 

The     average     yield     of     8 
samples  is  given  as  18.13  per 
cent. 

1 

Patch 

i    Represents  yield  of  total  ex- 
1       tractive  matter. 

J 

1907 

16.20  to 
26.50 

15.0  to 
25.20 

Total   alcoholic  extract.     Re- 

1908 

sults  obtained  in  the  exam- 
ination of  10  samples  of  cap- 
sicum. 
Total  alcoholic  extract. 

1908 

Vanderkleed 

jSolvent(?) 
1  11.59  to  18.35 

14.34  to  17.95 

j     Benzene 
1  14.00to  15.40 

Reported  as  yield  of  oleoresin : 

1909 

Represents  the  yield  from  3 
samples  of  capsicum. 

1910 

Southall  Bros.  & 
Barclay 

Results  obtained  In  the  ex- 
traction of  5  samples  of  cap- 
sicum. 

1910 

Eldred 

11.00  to 
26.00 

Ueported    as    yield   of     ether 

i9ia 

Vanderkleed 

J  Solvent(?) 
\  15.10  to  22.27 

soluble  oleoresin.    The  aver- 
erage  yield  obtained  from  48 
samples  of  capsicum  Is  given 
as  18.00  per  cent. 

Reported  as  yield  of  oleoresin. 
Results  obtained  In  extract- 
ing 7  samples  of  capsicum 

120 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


Table  31. —  Yield  of  oleoresin  as  reported  in  the  literature — Continued. 


Observer 

Yield  of  oleoresin  to 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1911 

Vanderkleed— 
Continued. 

Johnson  and 
Jolinson 

Per  ct. 

Per  ct. 

Per  ct. 

Percent. 

\    Solvent  (?) 
\        14.70 
\        17.93 

1    Reported    as    .yield  of  oleo- 
resin. 

1912 

16.00  to 
19.00 

J 
Reported  as  yield  of  ether  ex- 

1912 

Vanderkleed 



J    Solvent(?) 
(14.41  to  16.70 

tract. 

Reporte<l  as  yield  of  oleoresin. 
Total  alcoholic  extract.     Re- 

1913 

Patch 

19.00  to 
24.00 

.!!!!!!. 

1913 

Vanderkleed 

J   Solvent  (?) 
I  13.10  to  18.10 

Solvent(?) 
11.00 
11.30 
13.10 
14.80 
15.26 
I       15.80 

sults  obtained  in  extracting 
4  samples  of  capsicum. 

Reported  as  yield  of  oleoresin. 

1913 

Englehardt 

Seven   samples  of   capsicum 
were  extracted. 

1 

Rippetoe 



1 

\  Reported  as  yield  of  oleoresin. 

1914 

17.02  to 
24.46 

31.90  to 
35.30 

16.49  to 

17.88 

Total  yield  of  extract. 

1914 

Riedel 

Total  yield  of  extract. 

1914 

Vanderkleed 

J  Solvent(?) 
(  13.00  to  18. 00 

j  SolventC?) 
113.85  to  20. 84 

Reported  as  yield  of  oleoresin . 

1915 

Vanderkleed 



The  average   yield    from  15 
samples  is  given  as  10.00  per 
cent. 

The     average     yield     of     6 
samples  is  given  as  16.65  per 
cent. 

Table  32 — Yield  of  oleoresin  obtained  in  the  laboratory. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks     . 

1910.. 
1916.. 

DuMez  &  Netzel. 
DuMez 

Per  ct. 
25.12 

29.90 
16.40 

Per  ct. 

20.25 

22.48 
17.50 

Per  ct. 
18.33 

19.98 
16.14 

Per  cent. 

J  Benzine 
116.50 

fPetrol. 
J  Ether. 
118.82 

ct. 

tl6.18 

Represents  oleoresin  separated 

from  deposited  fat  and  other 
extractive  matter. 

OLEORESIN  OF  CAPSICUM  121 

Chemistry  of  the  Drug  and  Oleoresin. 

Tabulation  of  Constituents. 

The  reported  analyses^  of  the  various  varieties  of  red  peppers 
show  the  constituents  of  pharmaceutical  interest  to  be  as  fol- 
lows: fixed  oil,  volatile  oil,  fatty  acids,  capsaicin,  capsicine, 
resin,  mudilage,  starch,  coloring  matter  and  inorganic  sub- 
stances. Most  of  these  substances  have  been  identified  in  the 
oleoresin  prepared  by  extracting  the  fruits  with  ether.  They 
are  the  following: 


Fatty  Oil 

Capsaicin 

Coloring  Matter 

Fatty  Acids 

Capsicine 

Ash 

Volatile  Oil 

Eesin 

Occurrence  and  Description  of  Individual  Constituents. 

Fatty  Oil.  Work  on  the  oil  of  capsicum  has  practically  been 
limited  to  that  obtained  from  the  variety  official  in  most  of  the 
continental  pharmacopoeias,  namely:  Capsicum  annum  L.  The 
properties  of  the  oil  of  Capsicum  fastigiatum  Bl.  as  observed  by 
Goetz  appears  to  indicate  that  it  is  very  likely  identical  with 
the  former.^  The  oil  as  obtained  from  the  seeds  of  Capsicum 
annum  BU  is  a  yellowish  brown,  mobile  liquid,  specific  gravity 
15.5°C  0.91095;  iodine  value  (Huebls)  119.5;  saponification 
value  (Koettsdorffer)  187.2.  It  is  composed  of  the  glyceryl 
esters  of  oleic,  palmitic  and  stearic  acids. 

The  oil  of  capsicum  is  located  in  the  seeds  and  is  variously 
stated  to  comprise  from  20*  to  24.06^  per  cent,  of  these  organs 
in  Capsicum  annum.  The  yield  as  computed  by  Goetz  for  the 
entire  fruit  of  Capsicum  fastigiatum  is  8.4  per  cent..  The  yield 
in  the  case  of  Capsicum  fructescens  does  not  appear  to  have  been 
determined. 


*  Taylor,  Am.  Journ.  Fharm.  (1857),  29,  p.  303;  Buchheim,  Vierteljahrschr. 
f.  prakt.  Pharm.  (1872),  4,  p.  507;  Free.  A.  Ph.  A.  (1873),  22,  p.  106; 
Strohmer,  Chem.  Centralb.  (1884),  55,  p.  557;  Pabst,  Arch.  d.  Pharm.  (1892), 
230,  p.  108  ;  Tolman  and  Mitchell,  Bull.  No.  163,  Bur.  of  Chem.,  Dep.  of  Agr. 
(1913),  p.  9. 

*  Goetz  obtained  15.7  per  cent  of  a  yellowish-brown  fixed  oil  from  the 
seeds  of  Capsicum  fastigiatum  BL,  specific  gravity  at  25",  0.919.  Goetz,  un- 
published results. 

3  Buchheim,  I.  c;  Pabst,  I.  c;  von  Bitto,  Landwirt.  Versuchs-Stat.  (1896). 
46,  p.  310;  Meyer-Essen,  Chemiker  Ztg.   (1903),  27,  p.  958. 

*  Meyer-Essen,  I.  c. 
■von  Bitto,  I.  c. 


122 


DU  MEZ— THE  GAUENICAL.  OL.EOKESINS 


Fatty  Acids.^  The  free  fatty  acids  present  have  been  iden- 
tified as  oleic,  palmitic  and  stearic,  palmitic  acid  predominating 
in  the  fruits  of  Capsicum  annum.  The  proportions  of  these 
acids  as  they  occur  in  the  fruit  of  Capsicum  fastigiatum  or  C. 
fructescens  have  apparently  not  been  determined  to  date. 

Volatile  Oil.  The  presence  of  a  volatile  oil  was  first  noted  in 
the  fruits  of  Capsicum  annum  by  Taylor."^  Pabst  isolated  a 
small  amount  of  a  volatile  liquid  having  the  odor  of  parsley 
from  the  same.  Inasmuch  as  the  oleoresin,  when  prepared 
from  Capsicum  fructescens  has  a  distinct  odor,  it  is  quite  prob- 
able that  a  similar  volatile  oil  is  also  present  in  the  fruit  of 
this  variety. 

Capsaicin^  Capsaicin  is  the  sharp  tasting  constituent  of  the 
fruits  of  the  various  varieties  of  red  pepper.  It  crystallizes 
from  petroleum  ether  in  colorless  plates  melting  at  60.5° C 
(Morbitz),  63  to  63.5°C  (Micko),  64.5°C  (Nelson) .^«  The  sub- 
stance is  stated  to  be  soluble  in  water  (1:30,000),  petroleum 
ether  (1:3,633),  ether,  alcohol,  carbon  disulphide  and  chloro- 
form. According  to  Morbitz,  its  composition  is  represented 
by  the  formula  C35H54N3O4.  Micko^^  does  not  agree  with  the 
latter  and  has  proposed  the  formula  ,CH30.Ci7H24NO.OH,  as 
also  representing  the  structure  in  part.  . 

Capsaicin  is  stated  by  Morbitz  to  be  present  in  the  fruit  of 
Capsicum  fastigiatum  to  the  extent  of  0.05  to  0.07  per  cent. 


« Buchheim,  Pabst,  von  Bitto,  I.  c. 

U.  c. 

»  The  term  capsicin  was  first  used  to  designate  the  sharp  tasting-  principle 
principle  in  red  peppers.  Bucholz,  Taschenb.  f.  Scheidkuenst.  u.  Apoth. 
(1816),  37,  p.  1;  Landerer,  Vierteljahresschr.  f.  prakt.  Pharm.  (1854),  i, 
p.  34.  The  name  was  also  applied  to  the  ethereal  extract  of  capsicum  as 
marketed  by  Merck  and  Co.  See  note  by  Buchheim,  Vierteljahrschr.  f.  prakt. 
Pharm.  (1873),  22,  p.  507.  Later  it  was  used  to  indicate  a  coniine-like 
alkaloid  isolated  from  the  fruit  of  Capsicum  fastigiatum  by  Thresh.  Pharm. 
Journ.    (1876),   35,  p.  941. 

In  1873,  Buchheim  gave  the  name  Capsicol  to  a  dark  red  oily  liquid  (our 
present  oleoresin)    which  he   considered  to  be   the   pungent   principle. 

Capsaicin  is  the  term  which  was  Introduced  by  Thresh  to  denote  the  sharp 
tasting  substance  isolated  by  him  from  the  fruits  of  Capsicum  fastigiatum. 
Pharm.  Journ.  (1876),  36,  p.  21.  It  is  the  name  now  generally  employed  to 
indicate  this  substance,  although,  Morbita  (I.  c.)  subsequently  proposed  the 
name  Capsicutin. 

A  more  recent  investigator,  Gabriel  de  la  Puerta,  has  given  the  name 
"capsic  acid"  to  the  irritant  principle  isolated  ffom  pimenta.  Ann.  de  la 
Soc.  Espanola  de  fls.  y.  quim.  (1905),  No.  23;  Am.  Drugg.  &  Pharm.  Rec. 
(1906),  48,  p.  40. 

"Chem.  News   (1911,  103,  p.  111. 

"Chem.  Centralbl.    (1899),  70,  p.  293. 


OLEORESIN  OF  CAPSICUM  123 

The  amount  present  in  Capsicum  fructescens  has  not  been  re- 
ported. 

Capsicine.  According  to  Felletar^^  and  Thresh,"  capsicine 
is  present  in  the  fruits  of  Capsicum  annum  and  C.  fastigiatum. 
The  latter  describes  it  as  an  alkaloid  possessing  an  odor  simi- 
lar to  that  of  coniine.  The  hydrochloride  is  stated  to  have  been 
isolated  in  the  crystalline  form  and  to  be  precipitated  from 
aqueous  solution  by  the  usual  alkaloidal  reagents.  Pabst^* 
states  that  the  base  is  not  a  normal  constituent  of  the  fruits 
of  Capsicum  anniwi,  but  that  it  is  formed  when  the  latter  are 
stored  or  by  the  action  of  various  reagents. 

Resin.  Kesin  is  mentioned  by  several  investigators^^  as  a 
constituent  of  the  fruits  of  the  red  peppers.  Apparently  noth- 
ing has  been  done  toward  determining  its  composition  or  proper- 
ties. 

Coloring  Matter.  The  red  color  of  the  capsicum  fruit  as 
well  as  that  of  the  ethereal  extract  appears  to  have  attracted 
the  attention  of  all  investigators,  although,  Pabst,  is  the  only 
observer  who  attempted  to  identify  the  substance.  He  concluded, 
from  saponification  experiments,  that  it  was  a  cholesterin  ester 
of  a  fatty  acid.^^ 

AsTi.  According  to  von  Bitto,^^  the  ash  of  cap^cum  is  com- 
posed of  the  basic  elements,  K,  Na,  Mg,  Ca,  Fe,  Al  and  Mn 
combined  with  the  acid  radicles  CI',  SiOg",  SO/',  PO/",  NO3' 
and  CO3''. 

The  ash  content  of  red  pepper  varies  with  the  variety  of  the 
fruit.^^  That  of  the  commercial  drug  is  also  influenced  by 
the  presence  of  sand.  The  ash  of  Capsicum  fructescens  (sand 
free)  amounts  to  about  4.90  per  cent  of  the  dried  fruit.^* 


^2 Vierteljahrschr.  f.  prakt.  Pharm.  (1868),  17,  p.  360;  Buchner's  Hepert 
f.  d.  Pharm.   (1828),  27,  p.  35;   Froc.  A.  Ph.  A.,    (1871),  19,  p.  289. 

"Pharm.  Journ.    (1876),  35,  p.  941. 

"Z.  c. 

"Strohmer,  Pabst,  Tolman  and  Mitchell,  I.  c. 

"  Pabst,  I.  c. 

"Landw.  Versuchsstat.    (1893),  42,  p.  369. 

"  Tolman  and  Mitchell  give  the  ash  content  of  sand  free  Capsicum  annum 
as  6.69  to  7.54  per  cent.  Bull.  163,  Bur,  of  Chem.,  Dept  of  Agr.,  Washington, 
1913. 

"McKeown  gives  the  ash  content  of  Capsicum  fastigiatum  as  4.50  to  4.95 
per  cent.     Am.  Drugg.   (1886),  14,  p.  128. 

Tolman  and  Mitchell  report  the  sand  free  ash  content  of  Capsicum  fruc- 
tescens (African)  as  4.49  to  5.44  per  cent,  that  of  the  fruits  of  the  same 
variety  coming  from  Japan  as  4.60  to  5.35  per  cent,  I.  c. 


124  ^^  MEZ— THE  GALENICAL  OLEORESINS 


Constituents  of  Therapeutic  Importance 

The  early  investigators  assigned  the  intensely  irritating- 
properties  of  the  oleoresin  of  capsicum  to  various  substances 
supposed  to  be  contained  therein.  Bracconot^  and  Buchheim^ 
thought  it  due  to  the  oily  constituents,  Felletar^  attributed  the 
action  to  a  liquid  organic  base,  and  Pabst*  to  a  resin  intimately 
mixed  with  the  red  pigment.  The  irritating  principle  is  now 
known  to  be  the  crystalline  con^ituent,  capsaicin.^  The  latter 
has  not  been  isolated  in  sufficient  quantities  to  permit  of  an. 
extensive  investigation  of  its  physiological  properties.  It  is^ 
however,  known  to  act  as  a  rubefacient  when  applied  exter- 
nally, and  to  be  extremely  pungent  to  the  taste,  its  sharpnesa 
being  perceptible  in  aqueous  solution,  1  part  to  11  million, 
parts  of  water.* 

Physical  Properties 

Color:  The  color  of  the  oleoresin,  when  the  latter  i» 
spread  out  in  a  thin  layer  on  a  white  porcelain  surface,  is  a 
characteristic  light  brownish-red.  The  descriptions  of  th© 
color  given  in  pharmaceutical  literature  vary  to  a  considerable 
extent  (light  reddish-brown  to  dark  brown)  owing  very  likely  to 
a  difference  in  the  conditions  under  whieh  the  observations  were 
made. 

Odor:  The  odor  of  the  preparation  is  rather  faint,  but  char- 
acteristic, resembling  that  of  the  red  peppers. 

Taste:  It  is  extremely  pungent  and  should  be  tasted  with 
caution.  The  taste  is  usually  described  as  being  hot  and  fiery; 
or  burning. 

Consistence:  The  consistence  of  the  oleoresin  varies  with  the 
amount  of  solid  fats  (palmitin  and  stearin)  present,*^  and  with 

*Ann.   Chlm.  Phys.    (1817),  6,  p.  122. 

» Vierteljahresschr.  f.  prakt.  Pharm.    (1873),   22,  p.   507. 

^Ihid.  (1868),  17,  p.  360. 

*Arch.  d.  Pharm.    (1892),  230,  p.  108. 

"Micko,  Zeitschr.  f.  Unters.  Nahr.-u.  Genussm.   (1898),  12,  p.  215. 

•Morbitz,  Pharm.  Zeitschr.  f.   Russland,    (1897),  p.  372. 

'  See  under  "Methods  of  preparation".  : 


OLEORESIN  OF  CAPSICUM 


125 


the  temperature.  At  ordinary  temperatures  the  degree  of 
fluidity  is  usually  such  that  it  can  be  readily  poured.  It  should 
be  homogeneous  and  not  contain  a  deposit  of  fat. 

Solubility:  The  oleoresin,  when  prepared  with  ether,  is 
soluble  in  acetone,  ether,  chloroform,  carbon  tetrachloride,  car- 
bon disulphide,  petroleum  ether,  oil  of  turpentine^  and  solu- 
tions of  the  caustic  alkalies.  It  should  not  be  soluble  to  any 
great  extent  in  90  per  cent,  alcohol,  solubility  therein  indicating 
that  alcohol  was  the  menstruum  used  in  the  preparation  of  the 
oleoresin. 

Specific  gravity:  The  specific  gravity  of  the  oleoresin  de- 
termined at  25  °C  was  found  to  be  0.925  to  0.932  when  ether  was 
the  solvent  employed  in  extracting  the  drug.  When  alcohol 
or  acetone  were  employed  for  this  purpose,  the  results  were 
almost  the  same,  whereas  petroleum  ether  yielded  a  product 
of  low  specific  gravity.  The  low  specific  gravity  observed  in  the 
one  case,  where  acetone  was  used  in  the  preparation  of  the  oleo- 
resin, was  not  due  to  the  nature  of  the  solvent,  but  to  the 
more  complete  removal  of  the  solid  fats.  The  variation  in  the 
amounts  of  the  latter  retained  in  the  finished  product  is  thought 
to  be  the  chief  factor  infiuencing  the  specific  gravity  of  this 
preparation.  In  the  case  of  the  commercial  samples,  how- 
ever, the  presence  of  unevap orated  solvent  must  also  be  taken 
into  consideration  as  is  shown  in  the  tables  which  follow: 

Table  S^Specific  gravities  of  oleoretins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity 

1 

1910 
1916 

DuMez  &  Netzel 

Alcohol 

At25°C 
0.932 

2 

0.933 

3 

>(                «« 

Ether 

0.932 

4 

4.                .. 

Benzine 

0,925 

1 

DuMez 

Alcohol 

0.926 

2        

Acetone 

0.919 

■3 

" 

Ether 

0.925 

4      

" 

Petrol,  ether 

0.914 

King's  American  Dispensatory   (1900),  p.  1331. 


126 


DU  MEZ— THB  GALENICAL  OLiEORESINS 


Table  34 — Specific  gravities  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
gravity 

1 

1916 

DuMez     

Squibb  «&  Sons 

At  25°  C 
0.9101 

2 

Lilly  «&  Co 

0.919 

3 

»i 

Sharp  &  Doiitne 

0.928 

* 

1      taine  d  ether 

Refractive  index:  Determinations  made  in  the  laboratory 
show  that  the  oleoresin  should  have  a  refractive  index  of  about 
1.47  when  observed  at  25° C.  A  refractive  index  lower  than 
this  was  found  to  be  due  to  the  presence  of  unevaporated  solvent. 
The  solvent  employed  in  extracting  the  drug  or  the  variation 
in  solid  fat  content  appears  to  have  very  little  influence,  if 
any,  on  this  constant.  The  results  obtained  in  the  laboratory 
in  the  examination  of  the  oleoresin  follow: 

Table  ^6— Refractive  indices  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractive 
index 

1910 
1916 

DuMez  &  Netzel 

Alcohol 

At  25°  C 
1  463 

2 

1  477 

'4 

Ether 

1  474 

4 

" 

Petrol,  ether 

1  47.5 

DuMez 

Alcohol 

1  473 

2 

1.473 

»* 

Ether  

1  474 

»» 

Petrol,  ether 

1  472 

Table  36 — Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1  

1916 

DuMez  

Lilly  &  Co  

At  25°  C 
1  472 

2  

1.473 

3  

'< 

Sauibb  &  Sons 

1  467' 

*  Contained  ether. 


OLEORESIN  OF  CAPSICUM 


127 


Chemical  Properties. 

Loss  in  weight  on  heating:  Determinations  made  in  the 
laboratory  show  that  the  oleoresin  loses  but  little  in  weight  on 
heating  at  110 °C,  a  loss  of  but  0.42  to  2.13  per  cent,  having 
been  observed  for  the  preparation  when  free  from  solvent.  The 
laboratory  preparations  as  a  rule  showed  a  smaller  loss  than 
the  commercial  samples,  which  is  very  likely  due  to  a  difference 
in  the  temperature  conditions  under  which  the  preparations 
were  made.  The  results  obtained  in  the  determinations  made 
in  the  laboratory  are  given  in  the  following  tables : 

Table  ^1  —Laboratory  preparations — loss  in  iceight  on  heating 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent,  of 
loss  on 
heating 

1 

1916 

DuMez  

Alcohol 

At  110°  € 
0.42 

2 

•• 

Acetone 

0  52 

3 

Ether 

0.88 

4 

.      : 

Petrol,  ether 

0.68 

5 

" 

Alcohol 

5.15' 

6  .... 

Acetone 

0  74 

7 

4(     • 

Ether 

2  09 

8 

" 

Benzine 

1  01 

Contained  alcohol. 


Table  38. — Commercial  oleoresins — loss  in  weigJit  on  heating. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent  of 
loss  on 
heating 

1 

1916 

DuMez  

Sharp  &  Dohme . 

At  110°  C 
1  93 

2  

Lill.v&  Co 

Squibb  &  Sons..     . 

2.13 

3 

" 

4  09  > 

*  Contained  ether. 


Ash  Content:  The  determinations  made  in  the  laboratory 
show  that  the  ash  content  of  the  oleoresin  varies  with  the  solvent 
employed  in  its  preparation.  When  acetone  was  the  solvent 
used,  the  amount  of  ash  obtained  did  not  exceed  0.26  per  cent, 
whereas,  the  amount  was  only  0.09  to  0.12  per  cent,  when  the 
oleoresin  was  prepared  with  ether.  The  variable  results  ob- 
tained in  the  examination  of  the  commercial  samples  appear  to 


128 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


indicate  the  use  of  different  solvents  in  their  preparation.  The 
comparatively  high  value  (0.40  per  cent.)  obtained  in  one  case, 
however,  may  have  been  due  to  the  copper  present.  The  ash 
content  of  the  samples  examined  in  the  laboratory  is  given  in 
the  tables  which  follow: 


Table  39 — AsJi  contents  of  oleorsins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent, 
of  ash 

1 

1916 

DuMez 

Alcohol 

0.39 

2 

Acetone 

0.26 

3 

Ether 

Petrol,  ether 

0.09 

4 

»» 

0  09 

5  

;;    

0.39 

6 

Acetone 

0.24 

7 

" 

Ether  

0.12 

8  

0.10 

Tabe  40 — Ash  contents  of  commercial  oleoresins 


Sample 
No. 

Date 

Observer 

.Source 

Per  cent,  of 
ash 

Foreign 
constituents 

J 

1916 

DuMez  

Sauibb  &  Sons 

0.091 
0.40 
0.30 

2 

Sharp  &  Dohme 

Lilly  &  Co 

Copper 

3 

" 

^  Contained  ether. 


Acid  number:  The  acid  numbers,  when  acetone,  ether,  or 
petroleum  ether  were  used  in  the  preparation  of  the  oleoresin, 
were  found  to  be  106.6,  103.8  and  105  respectively.  When 
alcohol  was  employed  for  this  purpose,  the  value  obtained  for 
this  constant  was  considerably  lower,  being  93.5.  With  respect 
to  the  commercial  samples  examined,  the  acid  number  was  in 
all  cases  found  to  be  much  lower.  This  is  thought  to  be  due, 
in  two  instances,  to  a  low  free  acid  content  (principally  pal- 
mitic acid)  of  the  drug  from  which  the  oleoresins  were  pre- 
pared, or  to  the  more  complete  removal  of  these  acids  in  the 
separation  of  the  deposited  material.  In  the  third  case,  it 
was  caused,  in  part,  at  least,  by  the  presence  of  unevaporated 
solvent.  The  acid  numbers  obtained  for  the  preparations  ex- 
amined in  the  laboratory  are  as  of  Hows: 


OLBORESIN  OF  CAPSICUM 


129 


Table  41- Acid  numbers  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Acid 
number 

1 

2 

3 

4 

1916 

T)iiMp7 

93.5 

Acetone 

106.6 

ii        

Ether 

103.8 

.4        

Petrol.  Ether 

105.0 

Table  42 — Acid  numbers  of  commercial  oleoresins. 


1  Contained  ether. 


Sample 
No. 

Date 

Observer 

Source 

Acid    , 
number 

1  

2 

3 

1916 

DuMez              

Sauibb  &  Sons 

30.81 

Sharp  &Dohme 

60.3 

it        

Lilly  &  Co 

82.7 

Saponification  value:  The  saponification  values  obtained  for 
the  oleoresins  prepared  in  the  laboratory  were  above  200,  as  a 
rule,  regardless  of  the  nature  of  the  solvent  used  in  extracting 
the  drug.  The  comparatively  slight  variations  observed  were 
very  likely  due  to  the  difference  in  the  degree  to  which  the 
solid  fats  (principally  palmitin)  had  been  removed.  This  also 
accounts  for  the  comparatively  low  values  obtained  for  the 
commercial  preparations.  The  exceptionally  low  value  ob- 
tained for  the  sample  from  Squibb  and  Sons  is  to  be  attributed 
to  the  presence  of  unevaporated  solvent.  The  values  obtained 
for  the  preparations  examined  in  the  laboratory  are  given  in. 
the  tables  which  follow: 


Table  43 — Saponification  values  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Saponifica.- 
tion  value 

1916 

DuMez .        

Alcohol 

203  5 

Acetone 

209.2 

Ether 

207  4 

Petrol,  ether 

208.6 

Alcohol 

196  7 

Acetone 

202,8 

•J 

Ether 

206,9 

Benzin 

198  7 

130 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  44 — Saponification  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

1 

1916 

DuMez 

Squibb  &  Sons 

193.4' 
196  9 

2 

3 

«■ 

Lilly  &  Co 

198  3 

*  Contained  ether. 

Iodine  value:  An  iodine  value  of  122  to  123.9  was  obtained 
for  the  oleoresins  prepared  in  the  laboratory  using  ether  as  the 
•extracting  menstruum.  Results  very  near  the  same  were  ob- 
tained when  acetone  or  petroleum  ether  were  the  solvents  used, 
whereas,  the  preparation  when  made  with  alcohol  gave  a  lower 
value,  109.3  to  105.7.  The  principal  cause^  for  the  variation 
in  this  constant  (aside  from  the  effect  which  the  quality  of  the 
drug  or  the  solvent  may  have  thereon)  as  observed  in  the  case 
of  some  of  the  laboratory  preparations,  as  well  as  the  commercial 
samples,  is  thought  to  be  the  difference  in  the  degree  to  which 
the  saturated  fats  (principally  palmitin)  have  been  removed. 
In  the  case  of  one  of  the  commercial  samples,  however,  the 
low  iodine  value  is  to  be  attributed  to  the  presence  of  unevap- 
orated  solvent.  The  results  obtained  in  the  determinations 
made  in  the  laboratory  together  with  those  reported  by  Kebler 
for  the  total  ether  extract  are  given  in  the  tables  which  follow: 


Table  45 — Iodine  values  of  laboratory  preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Iodine 
value 

\ 

1913 
1916 

Keblera    

Ether 

107. 

2        

\2%A 

3 

»• 

•« 

\2^  2 

4 

•' 

•' 

127.3 

5 

«' 

»« 

132  0 

6 

" 

" 

137.3 

7        

" 

138  0 

8-24 

•' 

" 

110.0  to  14-5.7 
11.5.7 

1        

DuMez  

Alcohol 

2 

Acetone 

125.2 

8     

" 

Ether 

122.0 

4 

'• 

Petrol.  Ether 

123.7 

1     

«♦ 

Alcohol  

109  3 

2 

'• 

Acetone 

118.0 

3 

♦» 

Ether 

102  9 

4        .  ... 

»« 

Benzin 

116  9 

<a)  Kebler's  results  represent  the  iodine  value  of  the  total  ether  extract. 


*Lowenstein  and  Dunn  have  shown  that  heating  at  110°  C.  to  remove 
volatile  matter  from  the  total  ether  extract  causes  a  lowering  in  the  iodine 
value  due  to  absorption  of  oxygen  by  the  unsaturated  fats.  Journ.  Indust. 
And  Eng.  Chem.   (1910),  2,  p.  48. 


OLEORESIN  OF  CAPSICUM 


lai 


Table  46. — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Iodine 
value 

1 

1916 

DaMez   

Squibb  &  Sons 

Sharp  &  Dohme 

109.2  (1) 

2 

116.2 

3. 

" 

Lilly  &    Co 

121.7 

Contained  ether. 


Special  Quantitative  Tests. 

PJiysiological  Test. 

As  the  active  constituent  is  present  in  the  oleoresin  in  such 
minute  quantities  that  a  gravimetric  method  for  Its  estimation 
is  not  practical  at  the  present  time,  a  physiological  method  would 
appear  to  be  the  best  means  to  employ  in  the  standardization 
of  this  preparation.  Such  a  method  is  reported  to  be  in  use 
for  this  purpose  by  the  H.  K.  Mulford  Company.  Aside,  how- 
ever, from  the  fact  that  the  test  is  based  on  the  ability  to  de- 
tect the  pungency  of  the  oleoresin  in  extremely  dilute  solutions, 
and  that  the  firm  takes  as  its  standard  a  preparation  which  is 
still  pungent  to  the  taste  in  a  maximum  dilution  of  1  to  150,000, 
there  is  no  exact  information  available  to  show  in  what  man- 
ner  the  same  is  actually  carried  out.  It  is  thought,  however,, 
that  a  procedure  similar  to  that  developed  in  this  laboratory 
some  years  ago  (1910)  is  made  use  of.  The  following  is  a 
description  of  this  method. 

Accurately  weigh  about  1  drop  of  the  oleoresin  contained  in  a  small 
flask,  add  5  cubic  centimeters  of  normal  potassium  hydroxide  solution  and 
heat  on  a  water  bath  for  a  short  time  to  saponify  the  fats.  Transfer 
the  saponified  material  to  a  100  cubic  centimeter  flask,  using  several  por- 
tions of  water  for  this  purpose,  and  finally  dilute  up  to  the  mark  with 
more  water.  With  the  aid  of  a  pipette,  measure  off  5  cubic  centimeters 
of  this  solution  and  run  it  into  a  graduated  cylinder  (glass  stoppered)  of 
1,000  cubic  centimeters  capacity.  Dilute  this  with  water  added  in  por- 
tions of  100  cubic  centimeters,  tasting  the  solution  after  each  addition. 
Note  the  highest  dilution  in  which  the  pungent  taste  is  still  distinctly  per- 
ceptible and  compare  this  with  the  results  obtained  using  a  standard 
preparation. 

As  all  of  the  samples  prepared  in  this  laboratory  were  found 
to  be  distinctly  pungent  to  the  taste  in  dilutions  of  1  to  250,000, 


232  ^U  MEZ— THE  GALENICAL  OLEORESINS 

it  is  thought  that  the  standard  employed  by  the  H.  K.  Mulford 
Company  is  rather  low.  In  view  of  these  observations,  it  would 
appear  that  a  standard  of  1  in  200,000  would  be  more  desirable. 

Adulterations 

A  trace  of  copper  was  found  in  most     of    the    commercial 
samples  examined.      See  under  "Ash  content.'' 

OLEORBSIN  OF  CUBEB 
Synonyms 

Aetherisches  Cvibebenextrdkt,  Bern.  P.  1852. 

Aether-szeszes  Tcuheba  hivonat,  Hung.  P.  1888. 

Cubehen  Extrdkt,   Nethl.   P.    1902. 

Estratto  di  Cubehe,  Swiss  P.  1907. 

Estratto  di  Pepe  Cubehe,  Swiss  P.  1865. 

Estratto  di  Pepe  Cubebe  Etereo,  Ital.  P.  1902. 

Ethereal  Extract  of  Cubeb,  Am.  Journ.  Pharm.   (1846),  18,  p.  167. 

Extract  van  Staartpeper,  Nethl.  P.  1871. 

Exiractu  de  Cubebe,  Eoum.  P.  1874. 

Extractum  Cubebae  Fluidum,  U.  S.  P.  1850. 

Extractum  Cubebarum,  Aust.  P.   1906. 

Extractum,  Cubebarum  aethereum,  Swiss  P.  1865. 

Extractum  Cubebarum  aethereo-spirituosuw,  Hung.  P.  1888. 

Extractum  Cubebarum  oleoso-resinosum,  Strump,  AUg.  P.  1861. 

Ecitractum  Kubebae  oleo-resinosum,  Pruss.  P.  1829. 

Extrait  de  Cubebe,  Fr.  P.  1884. 

Extrait  ether^  de  Cubebe,  Bern.  P.  1852. 

Extrait  oUo-s^sineux  Cubebe,  Fr.  P.  1884.  ; 

Fluid  Extract  of  Cubebs,  U.  S.  P.  1850. 

Kubebe  Extract,  Dan.  P.  1869. 

KubebenextraM,  G.  P.  1872. 

KubeberextraTct,  Dan.  1893. 

Kubeba  Kivonat,  Hung.  P.  1875. 

Oelig-Harziges  KubebenextraTct,  Strump,  Allg.  P.  1861. 

Oleo-Resin  of  Cubebs,  B.  P.  1885. 

Oleo-Besina  Cubebae,  B.  P.  1885. 

Oleoresina  Cubebae,  U.  S.  P.  1910. 

OUoresine  de  Cubebe,  U.  S.  Disp.  1907. 

Oleoresinous  Extract  of  Cubeb,  Pareira,  Mat.  Med.  1854. 

History 

The  oleoresin  of  cubeb,  prepared  by  extracting  the  drug  with 
ether  and  then  removing  the  latter  by  distillation,  was  first 


OLEORESIN  OF  CUBEB  133 

brought  to  the  attention  of  the  European  pharmacist  by  Haus- 
mann  in  1838.  Ten  years  previous  (1828),  however,  Dublanc 
in  France  and  simultaneously  Oberdoerffer  in  Germany  had 
made  known  a  similar  preparation  obtained  by  a  rather  long 
and  tedious  process  involving  the  distillation  of  the  drug  with 
steam  and  subsequent  extraction  of  the  marc  with  alcohol.  The 
latter  became  official  in  the  Prussian  Pharmacopoeia  of  1829 
and  in  the  Pharmacopoeia  of  Schleswig-Holstein  in  1846,  while 
the  former  first  received  official  recognition  in  the  Baden  Phar- 
macopoeia of  1841. 

Through  the  efforts  of  Procter,  a  preparation  similar  to  that 
made  by  Hausmann  was  introduced  into  the  United  States 
Pharmacopoeia  of  1850  under  the  title  Extr actum  Cuhehae 
Fluidum.  In  the  edition  of  1860,  this  title  was  changed  to 
•Oleoresina  Cuhehae.  The  preparation  official  in  the  United 
States  at  present  is  the  oleoresin  obtained  by  extracting  the 
cubeb  with  alcohol,  whereas,  that  which  is  given  recognition 
in  the  late  European  pharmacopoeias  is  the  product  obtained 
by  exhausting  the  drug  with  a  mixture  of  alcohol  and  ether. 

The  pharmacopoeias  of  the  countries,  states  and  municipali- 
ities  in  which  this  preparation  has  been  officially  recognized,  to- 
gether with  the  dates  of  appearance  of  the  various  editions  in 
which  it  received  such  recognition,  are  enumerated  below. 

Prussian  Pharmacopoeia  — 1829,  1833,  1868. 
Pharmacopoeia  of  Baden  —  1841. 
Pharmacopoeia  of  Schleswig-Holstein  —  1844. 
Pharmacopoeia  of  Berne — 1852. 
Belgian'  Pharmacopoeia — 1854,   1855. 

Qnited  States  Pharmacopoeia  —  1850,  1860,  1870,  1880,  1890,  1900,  1910. 
Pharmacopoeia  of  Hannover  —  1861. 
Pharmacopoeia  of   Hessen  —  1862. 
Swiss  Pharmacopoeia — 1865,    1872,   1893,    1907. 
Austrian  Pharmacopoeia  —  1869,  1889,  1906. 
Danish'   Pharmacopoeia — 1869,    1893. 
Hungarian  Pharmacopoeia  — 1871,   1888,  1909. 
Netherlands  Pharmacopoeia  —  1871,  1902. 
■German  Pharmacopoeia  — 1873,  1882,   1890,   1900,  1910. 
Roumanian  Pharmacopoeia  — 1874. 
French  Pharmacopoeia  —  1884,  1908. 

British'  Pharmacopoeia  —  1885.  ~ 

Italian  Pharmacopoeia  — 1902,1909. 
Japanese  Pharmacopoeia  — 1907. 


*  Not  official  In  the  recent  editions. 


234  I^U  MEZ— THE  GALENICAL.  OLEORESINS 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

The  drug  recognized  by  the  ninth  revised  edition  of  the 
United  States  Pharmacopoeia  is  'Hhe  dried,  unripe  fruits  of 
Piper  Cuheha  Linne  filius  (Fam.  Piperaceae),  without  the  pres- 
ence or  admixture  of  more  than  5  per  cent  of  stems  or  other 
foreign  matter."  Other  botanical  synonyms  for  the  same  fre- 
quently met  with  in  the  literature  are :  Cuheha  Cuheha  (Linne 
filius)  Lyons;  and  Cuheha  officinalis  Mique. 

The  fruit  is  supposedly  gathered  when  full  grown,  but  before 
ripe,  and  is  immediately  packed  for  exportation.  That  some 
of  the  fruit  for  sale  on  the  American  market  is  not  collected 
until  after  ripening  would  appear  to  be  the  case  from  the  color 
of  some  of  the  oleoresins  prepared  by  the  author,  a  condition 
which  has  also  been  noted  by  the  others.^  In  addition,  it  should 
also  be  noted  that  the  so-called  false  cuhehs^  are  sometimes  sub- 
stituted for  the  official  drug. 

As  cubeb  gradually  deteriorates  with  age,^  and  in  the 
powdered  condition  becomes  rapidly  weaker  owing  to  the  loss 
of  volatile  oil,  it  should  be  stored  whole,  in  closed  containers, 
and  powdered  only  as  it  is  used. 

U.  S.  P.  Text  and  Comments  Thereon. 

The  oleoresin  has  been  official  in  the  last  seven  editions  of  the 
Pharmacopoeia,  having  been  recognized  for  the  first  time  in  the 
edition  of  1850  under  the  title  Extractum  Cuhehae  Fluidum. 

1850 
Extractum  Cubebae  Fluidum 
Fluid  Extract  of  Cubebs 
Take  of  Cubebs,*  in  powder,'^  a  pound;    then  distill  off,  by  means  of  a  water- 
Ether  ^  a  sufficient  quantity.  bath,  at  a  gentle  heat,  a  pint  and  a 
Put  the  Cubebs  into  a  percolator,*    half  of    the    ether,"    and    expose  the 
and,  having  packed  it  carefully,  pour    residue,  in  a  shallow  vessel,  until  the 
Ether     gradually     upon  it  until  two    whole  of  the  ether  has  evaporated.^ 
pints  of  filtered  liquor  are  obtained;" 


1  Emanuel  (1894)  stated  that  when  he  reported  to  the  jobber  that  he  had 
obtained  a  brown  colored  oleoresin  from  the  cubeb  purchased,  the  latter 
replied  that,  while  the  United  States  Pharmacopceia  specified  the  unripe  fruit, 
this  was  rarely  found  on  the  market. 

2  The  botanical  origin  of  this  fruit  is  not  knoM'n.  Culbreth,  Materia  Medica 
and  Pharmacology   (1903),  p.  138, 

8  The  volatile  oil,  in  part,  is  converted  into  the  so-called  cubeb  camphor, 
especially  when  stored  in  a  damp  place.  Schmidt,  Ber.  d.  deutsch  chem, 
Ges.    (1877),  10,  p.  188. 


OLEORESIN   OF   CTJBBB 


135 


1860 

Oleoresina  Cubebae 
Oleoresin  of  Cubeb 
Extractum  Cubebae  Fluidum,  PJiarm.,  1850 
Take     of     Cubeb/     in     fine  powder,"   liquid  have  passed.^       Eecover   from 
twelve  troyounces;  this,  by  distillation  on  a  water-bath, 

Ether  *  a  sufficient  quantity.  eighteen    fluid-ounces    of    ether,*   and 

Put  the  Cubeb  into  a  cylindrical  expose  the  residue,  in  a  capsule,  until 
percolator,*  press  it  moderately,  and  the  remaining  ether  has  evaporated.' 
gradually  pour  Ether  upon  it  until  Lastly  keep  the  oleoresin  in  a  well- 
twenty-four    fluid-ounces     of     filtered    stopped   bottle." 


1870 
Oleoresina  Cubebae 


Oleoresin 
Take    of    Cubeb,^    in    fine    powder,^' 

twelve  troy-ounces; 
Ether '   a   sufficient   quantity. 

Put  the  Cubeb  into  a  cylindrical 
percolator,  provided  with  a  stop-cock, 
and  arranged  with  a  cover  and  recep- 
tacle suitable  for  volatile  liquids,* 
press  it  moderately,  and  gradually 
pour  ether  upon  it,  until  twenty-four 
fluidounces  of  liquid  have  slowly  pass- 


of  Cubeb 

ed.^  Eecover  the  greater  part  of  the 
ether  by  distillation  on  a  water-bath,* 
and  expose  the  residue,  in  a  capsule, 
until  the  remaining  ether  has  evapor- 
ated.'' When,  after  standing  in  a  close 
vessel,  the  liquid  has  deposited  a  waxy 
and  crystalline  matter,  decant  the 
oleoresin  *  and  keep  it  in  a  well-stop- 
ped bottle.* 


1880 

Oleoresina  Cubebae 
Oleoresin  of  Cubeb 


Cubeb,^  in  No.  60  powder,'  one  hun- 
dred  parts    100 

Stronger  Ether,'  a  sufficient  quantity. 
Put  the  Cubeb  into  a  cylindrical 
percolator,  provided  with  a  cover  and 
receptacle  suitable  for  volatile  li- 
quids,* press  it  firmly,  and  gradually 
pour  stronger  ether  upon  it,  until  one 
hundred  and  fifty  (150)  parts  of 
liquid  have  slowly  passed."  Eecover 
the  greater  part  of  the  ether  by  dis- 


tillation on  a  water-bath,"  and  ex- 
pose the  residue,  in  a  capsule,  until 
the  remaining  ether  has  evaporated.' 
Transfer  the  remainder  to  a  close  ves- 
sel, and  let  it  stand  until  it  ceases  to 
deposit  a  waxy  and  crystalline  mat- 
ter.      Lastly,  pour  off  the  oleoresin." 

Keep  the  oleoresin  in  a  well-stop- 
ped bottle." 

Preparation:     Trochisci  Cubebae. 


136 


DU  MEZ— THE  GALENICAL.  OLEOKEJSINS 


*^\ 


1890 

Oleoresina  Cubebae 
Oleoresin  of  Cubeb 


Cubeb/  in  No.  30  powder,'  -five  hun- 
dred grammes   500  Gm. 

Ether,^  a  sufficient  quantity. 

Put  the  Cubeb  into  a  cylindrical 
glass  percolator,  provided  with  a 
stop-cock,  and  arranged  with  a  cover 
and  receptacle  suitable  for  volatile 
liquids.*  Press  the  drug  firmly,  and 
percolate  slowly  with  ether,  added  in 
successive  portions,  until  the  drug  is 
exhausted.'  Eecover  the  greater  part 
of   the   ether  from   the  percolate   by 


distillation  on  a  water-bath,"  and,  hav- 
ing transferred  the  residue  to  a  cap- 
sule, allow  the  remaining  ether  to 
evaporate   spontaneously.'^ 

Keep  the  product  in  a  well-stop- 
pered bottle." 

NOTE.  Oleoresin  of  Cubeb  de- 
posits, after  standing  for  some  time, 
a  waxy  and  crystalline  matter,  which 
should  be  rejected,  only  the  liquid 
portion  being  used.' 

Preparation:     Trochisci  Cubebae. 


1900 


Oleoresina  Cubebae 
Oleoresin  of  Cubeb 


Cubeb,*  in  No.  30  powder,'  five  hun- 
dred grammes 500  Gm. 

Alcohol,'  a  sufficient  quantity. 

Introduce  the  cubeb  into  a  cylindri- 
cal glass  percolator,*  pack  the  powder 
firmly,  and  percolate  slowly  with  al- 
cohol, added  in  successive  portions, 
until  the  cubeb  is  exhausted."  Re- 
cover the  greater  part  of  the  alcohol 
from  the  percolate  by  distillation  on 
a  water-bath,"  and,  having  transferred 
the  residue  to  a  dish,  allow   the  re- 


maining alcohol  to  evaporate,  with 
constant  stirring,  in  a  warm  place.^ 
Keep  the  oleoresin  in  a  well-stoppered 
bottle." 

NOTE.  Oleoresin  of  cubeb  de- 
posits, after  standing  for  some  time, 
a  waxy  and  crystalline  matter,  which 
should  be  rejected,  the  liquid  portion 
only   being   used.* 

Average  dose.  —  0.500  Gm.  =  500 
milligrammes  (7^  grains.) 


OLEORBSIN  OF  CUBES  1^7 

1910 

Oleoresina  Cubebae 
Oleoresin  of  Cubeb 
Oleores.  Cubeb 

Cubeb/  in  No.  30  powder,^  iive  hun-  alcohol  to  evaporate,  in  a  warm  place, 

dred    grammes 500  Gm.  stirring   frequently/     Keep    the   oleo- 

Alcohol,^  a  sufficient  quantity.  resin  in  a  well  stoppered  bottle.' 

Place    the    cubeb    in    a    cylindrical  '  NOTE — Oleoresin    of    Cubeb,  after 

glass     percolator,*     pack  the  powder  standing    for    some   time,    deposits    a 

firmly,  and  percolate  slowly  with  alco-  waxy      and      crystalline      precipitate, 

hoi,  added  in  successive  portions,  until  which  should  be  rejected,  the  liquid, 

the  drug  is  exhausted."       Eecover  the  portion  only  being  used.* 

greater  part  of  the  alcohol  from  the  Preparation — Trochisci  Cubebae. 

percolate  by   distillation   on  a  water-  Average    Dose — Metric,    0.5  Gm. — 

bath,*  and,,  having     transferred     the  Apothecaries,  8  grains, 
residue  to  a  dish,  allow  the  remaining 

1)  For  a  description  of  the  drug,  see  page  1040  under  ''Drug 
used,  its  collection,  preservation,  etc." 

2)  The  last  three  editions  of  the  Pharmacopoeia  have  specified 
that  the  drug  used  be  reduced  to  a  No.  30  powder  for  perco- 
lation. Previous  editions,  with  the  exception  of  that  of  1850, 
directed  that  a  fine  powder  (No.  60)  be  used  for  this  purpose. 
In  the  Pharmacopoeia  of  1850,  the  degree  of  fineness  was  not 
specified.  The  coarser  powder  corresponds  more  nearly  in  its 
composition  to  that  of  the  whole  fruit  than  does  the  fine  pow- 
der, owing  to  the  fact  that  a  relatively  large  amount  of  vola- 
tile oil  is  lost  in  the  preparation  of  the  latter. 

3)  Previous  to  the  edition  of  1900,  the  Pharmacopoeia  speci- 
fied the  use  of  ether  for  extracting  the  drug,  whereas,  the  last 
two  editions  have  directed  that  alcohol  be  employed  for  this 
purpose.  The  fact,  that  the  latter  yields  a  product  differing 
but  slightly  in  its  physical  properties  from  the  oleoresin  ob- 
tained with  ether,  was  pointed  out  by  Procter  in  1866,  and 
later  confirmed  by  other  investigators.  Since  the  alcoholic 
preparation  appears  to  be  equally  as  efficient  from  a  therapeu- 
tic standpoint,  as  well,  the  change  from  ether  to  alcohol  ap- 
pears to  be  justified.  The  use  of  a  menstruum  consisting  of 
equal  parts  of  alcohol  and  ether,  as  specified  in  some  of  the 
foreign  pharmacopoeias,  the  Austrian,  German  and  Japanese, 


238  DU  MEZ— THE  GALENICAL.  OLEORESINS 

does  not  appear  to  offer  any  special  advantage  either  from  a 
pharmaceutic  or  therapeutic  standpoint. 

4)  In  the  Pharmacopoeias  of  1870,  1880  and  1890,t  he  drug 
was  directed  to  be  extracted  in  a  percolator  specially  adapted 
to  the  use  of  volatile  solvents.  See  Part  I  under  "Apparatus 
used."  With  the  change  in  menstruum  (ether  to  alcohol),  a 
special  form  of  percolator  was  no  longer  necessary,  and  the 
Pharmacopoeia  now  directs  that  an  ordinary  cylindrical,  glass 
percolator  be  used. 

5)  In  the  earlier  editions  of  the  Pharmacopoeia  (1850  to  1880 
inclusive),  it  was  directed  that  percolation  be  discontinued  short 
of  the  complete  exhaustion  of  the  drug,  the  object  evidently 
having  been  to  economize  in  the  use  of  the  relatively  expen- 
sive solvent,  ether.  With  the  reduction  in  the  price  of  the 
latter,  however,  the  economic  factor  diminished  in  importance 
and  as  a  result  the  Pharmacopoeia  of  1890  directed  that  perco- 
lation be  allowed  to  proceed  until  the  drug  was  exhausted. 
This  is  also  the  procedure  given  in  the  more  recent  editions  of 
.the  Pharmacopoeia,  in  which  alcohol  has  replaced  ether  as  the 
extracting  menstruum. 

In  this  connection,  it  is  desired  to  point  out  that,  whereas 
percolation,  when  ether  is  the  menstruum  used,  should  be  con- 
tinued to  complete  exhaustion  of  the  drug  in  order  that  the 
extraction  of  the  total  amount  of  therapeutically  active  con- 
stituents may  be  assured,  this  procedure  does  not  appear  to  be 
necessary  when  alcohol  is  the  solvent  employed.  While  this 
statement  is  not  in  conformity  with  the  present  pharma- 
copoeial  directions  governing  the  extraction  of  the  drug  and  is 
not  supported  by  direct  experimental  evidence,  it  is  thought 
to  be  justified  in  view  of  the  (ftfference  in  the  solubility  of  the 
therapeutically  active  resins  in  the  above  mentioned  men- 
strua. The  indifferent  resin  is  but  slightly  soluble  in  ether. 
It  will,  therefore,  be  extracted  but  slowly  by  this  solvent  and 
will  be  present  in  the  percolate  even  to  the  last  portions.  Al- 
cohol, on  the  other  hand,  dissolves  both,  the  acid  and  indiffer- 
ent resins  readily.  These  substances  should  therefore  be  con- 
tained in  tota  in  the  first  portions  of  the  percolate.  In  this 
case,  it  would  therefore  appear  that  the  continuation  of  the 
process  of  extraction  to  the  complete  exhaustion  of  the  drug 


OLEORBSIN  OF  CUBEB  139 

only  serves  to  load  the  percolate  with  undesirable  extractive 
matter  such  as  cubebin. 

6-7)  The  various  editions  of  the  Pharmacopoeia,  since  1870, 
have  directed  that  the  greater  part  of  the  solvent  be  removed 
from  the  percolate  by  distillation  on  a  water  bath,  and  that 
the  remainder  be  allowed  to  evaporate  spontaneously. 

Experience  in  the  laboratory  has  shown  that  it  is  impos- 
sible to  obtain  a  uniform  product,  when  operating  according 
to  the  above  directions,  unless  identical  conditions  are  main- 
tained in  each  case.  This  is  due  to  the  fact  that  a  compara- 
tively slight  variation  in  the  procedure,  with  respect  to  the 
quantity  of  the  solvent  removed  by  distillation  or  to  the  tem- 
perature at  w^hich  spontaneous  evaporation  is  allowed  to  pro- 
ceed produces  a  variation  in  the  volatile  oil  content  of  the  finished 
product,  which  in  turn  affects  its  physical  and  chemical  proper- 
ties. It  is  thought,  therefore,  that  the  amount  of  solvent  to  be 
removed  by  distillation,  as  well  as  the  temperature  at  which 
the  last  portions  are  to  be  removed,  should  be  definitely  stated 
by  the  Pharmacopoeia  in  order  that  a  more  uniform  product 
may  be  obtained. 

8)  For  a  statement  concerning  the  nature  of  the  precipitate 
which  forms  in  the  oleoresin  upon  standing,  see  page  1060  un- 
der '* Other  properties." 

Since  the  greater  part  of  the  precipitate  is  composed  of  ma- 
terial which  is  of  no  therapeutic  value,  it  should  be  removed 
before  dispensing  the  preparation  as  directed  by  the  Pharma- 
copoeia. 

9)  The  oleoresin  should  be  kept  in  well  stoppered  bottles  ow- 
ing to  the  fact  that  it  loses  volatile  oil  and  undergoes  other 
changes  on  exposure  to  the  air.  See  cubeb  camphor,  page 
1050. 


Yield 

The  amount  of  oleoresin  obtained  varies  to  a  considerable 
extent,  10  to  30  per  cent,  having  been  obtained  when  alcohol, 
acetone  or  ether  were  employed  as  menstrua  for  the  extraction 
of  the  drug.  When  petroleum  ether  is  the  solvent  made  use  of, 
the  yield  is  much  lower,  4  to  18  per  cent,  having  been  reported 
in  this  case.     Aside  from  the  effect  of  the  solvent,  the  principal 


2^40  I^U  MEZ— THE  GALENICAL  OLEORESINS 

factors  influencing  the  yield  appear  to  be  the  variation  in  the- 
volatile  oil  content  of  the  drug  from  which  the  oleoresin  is  pre- 
pared and  the  conditions  under  which  the  preparation  of  the 
latter  has  been  accomplished.  As  the  volatile  oil  content  of 
the  cubeb  fruit  is  stated  to  vary  from  10  to  18  per  cent.,  a  var- 
iation of  even  greater  magnitude  is  to  be  expected  in  the  amount 
of  oleoresin  obtained.  While  this  is  true  when  a  vacuum  pan  is 
employed  in  the  evaporation  of  the  solvent,  the  difference  is 
not  so  great  when  the  pharmacopoeial  directions  are  followed 
as  the  loss  in  volatile  oil  in  this  case  is  relatively  greater  when 
the  fruits  contain  a  large  amount  of  this  constituent  than  when 
only  a  small  amount  is  present.  The  difference  is  still  further 
decreased  when  the  solvent  is  evaporated  on  a  water  bath  under 
ordinary  atmospheric  pressures.  The  following  tables  show 
the  yield  of  oleoresin  obtained  with  the  use  of  various  solvents  r 


OLEORBSIN  OF  CTJBEB 


141 


Table  47  —  Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ethei 

Other 
solvents 

Remarks 

1846 

Bell                  ..   . 

Per 
cent 

Per 
cent 

Per 

cent 

15.0  to 

20.0 

21.90 

Per  cent. 

1868 

Procter  

27.00 

Benzin 

16.50 

Benzin 

5.00 

1867 

Pile 

Yield  to   ben/in,   .sp.    gr.     86" 
Baum6. 

1868 

TTfivdpnrplpVi 

23.75 

1877 

Griffin 

Gasolin 
16,50 

Benzin 
16.65 

1887 

Kremel 

30.00 



22.00 
21.26 

1888 

Trimble 

1892 

Rprincpr 

21.75 
24.10 
25.00 

Sherrard, 



3  The  cubebs  were  completely 

exhausted. 

1892 

16.40 
18.80 
21.06 
21.90 
23.00 
24.70 
24.80 
24.80 

22.45 

Hyers 

/ 

1895 

14.48 

18.48 

i     Petrol. 
\     Ether. 
\        13.47 
j  Solvent(?) 
(18.85  to  26.88 

22.08 

22.60 

21.13 

22.80 
j     Solvent(?'> 
1 13. 69  to  23.60 

3  Solvent  (?) 
(16.49  to  24.34 
f        Petrol 
Ether 
3.88 
4.30 
j        4.45 
1       14.00 
16.03 
16.. 54 
16.90 
I      18.08 
3    Sol  vent  (?) 
1l8.42to  24.40 

3  Solvent  (?) 
(        22.14 
Petrol 
<      Ether 
4.66  to  8.78 

1907 

Blome 

Reported  as  yield  of  oleoresin 

1907 

Evans  Sons, 
Lescher  &  Webb 

Vanderkleed .... 

Results  obtained  in  the  ex- 
traction    of    5     samples  of 
cubeb. 

■ 

1908 

Reported  as  yield  of  oleoresin. 

1909 

Results  obtained  in  the  ex- 
traction  of    4     samples    of 
cubebs. 

Reported  as  j'ield  of  oleoresin. 

1910 

Southall  Bros., 
&  Barclay 

On  subsPQuent  extraction  with 

Vanderkleed .... 

alcohol  3.40  to  5.66  per  cent. 

of  extractive  matter  was  ob- 

tained. 

1910 

Reported  as  yield  of  oleoresin. 

1911 

Vanderkleed .... 

Results  obtained  in  the  ex- 
traction   of    6     samples     of 
cubebs. 

Reported  as  yield  of  oleoresin. 

1911 

Southall    Bros. 
&  Barclay 

The  average  yield  of  5  samples 

of  cubebs  is  griven  as  6.95. 

142 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  47 — Yield  of  oleoresin  as  reported  in  the  literature — Continued. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1912 

Vanderkleed  . . . . 

Per 

cent 

Per 

cent 

Per 
cent 

Per  cent. 

J    Solvent  (?) 
117.36  to  24.49 

'    Solvent  (?) 
he. 00  to  22.00 
j   Solvpnt(?) 
/        21.18 

Alcohol  and 
■(        ether 

11.10  to  14.70 

Reported  as  yield  of  oleoresin 

1913 

Dohme  &  Engel- 
hardt 

Results  obtained  in  the  ex- 
traction   of     5     samples    of 
cubebs. 

Reported  as  yield  of  oleoresin. 

1913 

Vanderkleed  . . . . 

1914 

Riedel 

1914 

8.87  to 
11.04 

7.68  to 
9.80 

Results  obtained  in    the  ex- 

1914 

Scoville 

J   Solvent  (?) 
(18.1010  22.00 
J  Solvent(?) 
113.90  to  19.80 

traction     of    6     samples  of 
cubebs.      Reported    as     an- 
hydrous extracts. 

Reported  as  yield  of  oleoresin. 

1914 

Vanderkleed .... 



Reported  as  yield  of  oleoresin. 

Results  obtained  in  the  ex- 
traction   of     6     samples  of 
cubebs. 

Table  48 — Yield  of  oleoresin  as  obtained  in  the  laboratory. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1910 
1916 

DuMez  &  Netzel. 
DuMez 

Per 
cent 
27.09 

16.34 

Per 

cent 
26.07 

16.76. 

Per 
cent 
23.47 

15.28 

Percent. 
j      Benzin 
1         18.75 

(       Petrol 
\       Ether 
1        13.04 

Represents    the  yield  using  a 
Soxhlet's  extraction  app.,  ex- 
cept in  the  case  of  alcohol. 

Represents  the    vield  usingr  s 

Soxhlet's  extraction  app..  ex- 
cept in  the  case  of  alcohol. 

OLEORBSIN  OF  CUBEB  143 

Chemistry  of  the  Drug  and  Oleoresin, 

Tabulation  of  Constituents. 

We  are  indebted  principally  to  Bernatzik^  Schmidt^  and 
Schulze^  for  definite  information  concerning  the  constituents 
of  the  cubeb  fruit.  According  to  these  investigators,  the  con- 
stituents of  importance  from  a  pharmaceutical  standpoint  are 
as  follows:  volatile  oil,  fatty  oil,  fat,  cubebin,  cubebic  acid, 
indifferent  resin,  coloring  matter,  starch,  gum  and  inorganic 
substances.  Inasmuch  as  an  attempt  to  determine  the  compo- 
sition of  the  oleoresin  does  not  appear  to  have  been  made  since 
the  identification  of  the  above  enumerated  constitutents,  a 
definite  statement  concerning  its  exact  composition  can  not  be 
given.*  However,  a  knowledge  of  the  physical  properties  of 
the  constituents  of  the  fruit  warrants  the  statement  that  the 
following  are  present  in  the  oleoresin  when  prepared  with  alco- 
hol or  ether : 

Volatile  oil  Cubebin  Coloring  matter 

Fatty  oil  Cubebic  acid  (Acid  resin)         Ash 

Fat  Eesin  (Indifferent  resin) 

Occurrence  and  Description  of  Individual  Constituents 

Volatile  Oil.^  The  volatile  oil  of  cubeb  is  a  colorless  or  pale 
green,  thick  fluid  possessing  a  burning,  spicy,  but  not  a  bitter 
taste.  Its  specific  gravity  varies  (0.915  to  0.937  at  15°C)  de- 
pending on  the  age  of  the  oil  after  distillation  or  the  length 
of  time  that  the  fruits  have  been  stored  before  obtaining  the 
oil.     It  is   strongly  refractive  and  is  laevogyrate, — 39.45°   to 


iBuchner's  n.  Repert.  f.  d.  Pharm.  (1865),  14,  p.  97. 

a  Arch.  d.  Pharm.    (1870),  191,  p.   23. 

»Jhid.    (1873,   202,  p.   388. 

The  following  are  among  the  early  Investigators  who  have  reported  analy- 
ses of  the  fruit:  Trommsdorff,  Trommsdorff's  n.  Joum.  der  Pharm.  (1811), 
20,  p.  69;  Vauquelin,  Journ.  de  Chim.  Med.  (1820),  21,  p.  103;  Taschenb.  f. 
Scheidekuenst.  (1822),  p.  185;  Monheim,  Buchner's  Repert.  d.  Pharm.  (1833), 
44,   p.  199. 

*Vieth  in  an  article  on  the  relation  between  the  chemical  composition  and 
therapeutic  activity  of  various  balsams  states  that  Kubebenextrakt  consists 
of  terpenes  (25  per  cent.)  resin  acids  (10  per  cent.)  and  resins  (25  per 
cent.)  Verh.  d.  Ges.  deutsch.  Naturf.  u.  Aerzte   (1905),  2,  p.  364. 

•The  above  description  is  for  the  volatile  oil  obtained  from  the  fruits  by 
steam  distillation  and  corresponds  to  the  properties  as  observed  by  Schmidt, 
Arch.  d.  Pharm.    (1870),  191,  p.  18. 


244  DU  MEZ— THE  GALENICAL  OLEORESINS 

— 40.16°.  Alcohol,  ether,  carbon  disulphide,  petroleum  ether, 
chloroform  and  fatty  oils  dissolve  it  readily. 

The  investigation  of  the  composition  of  this  oil  has  been 
undertaken  by  a  number  of  workers.^  Oglialoro^  noted  the 
presence  of  a  small  amount  of  a  1-terpene  (pinene  or  camphene). 
Wallach^  isolated  dipentene  and  cadinene.  The  presence  of  the 
latter  has  been  confirmed  by  others.^  Cubeb  camphor^''  has  also 
been  obtained  from  certain  samples  of  the  oil.  It  is  a  sesqui- 
terpene hydrate  (C15H24H2O)  which  forms  when  the  fruits  are 
stored  in  a  damp  place  or  when  the  oil  is  exposed  to  a  moist 
atmosphere.  It  separates  out  in  the  form  of  rhombic  octahe- 
drons when  the  oil  is  cooled  at  a  low  temperature  (  - 12  to 
-14° C)  for  some  time. 

The  yield  of  the  oil  is  stated  by  Schimmel  &  Co.^^  to  be  from 
10  to  18  per  cent.  A  yield  as  low  as  0.4  per  cent,  has  been  re- 
ported.^^  Schmidt  obtained  14.215  per  cent,  from  fresh  cubebs 
and  13.041  per  cent,  from  stored  cubebs.^^ 

Fatty  Oil.  Schmidt^*  describes  the  fatty  oil  as  a  thick,  dark 
green  liquid  congealing  at  0°C.  It  is  stated  to  be  slowly  but 
completely  soluble  in  cold  alcohol,  more  soluble  in  hot  alcohol, 
readily  soluble  in  ether,  chloroform,  carbon  disulphide  and  fatty 
oils. 

The  yield  as  reported  by  the  above  investigator  is  1.175  per 
cent,  for  fresh  cubebs  and  1.096  per  cent,  for  fruits  which  have 
been  stored  for  some  time. 


"The  earliest  work  on  the  constituents  of  the  oil  is  that  of  Soubeiran  and 
Capitaine,  Ann.  d.  Chem.   (1840),  34,  p.  31. 
'Gaz.  Chim.  Ital.   (1875),  5,  p.  497. 
•Ann.  d.  Chem.   (1887),  238,  p.  78. 

»Schaer  and  Wyss,  Arch,  d.  Pharm.  (1875),  206,  p.  216;  Umney,  Pharm. 
Journ.    (1895),   25,  p.  951. 

"Blanchet  and  Sell,  Ann.  d.  Chem.  (1833),  6,  p.  294;  Winckler,  Buchner's 
Repert.  f.  d.  Pharm.  (1833),  45,  p.  397;  Bernatzik,  Buchner's  n.  Repert.  f. 
d.  Pharm.  (1865),  14,  p.  97;  Schmidt,  Ber.  d.  deutsch.  chem.  Ges.  (1877), 
10,  p.  188. 

"Schimmel  &  Co.,  Ber.    (1897),  p.  14. 

"Busse  reports  the  yield  of  volatile  oil  as  obtained  by  various  investi- 
gators as  follows : 

Baumfe    5.3     per  cent. 

Schoenwald    7.03  per  cent. 

OberdoerfPer     12.5     per  cent. 

Hager    0.4     per  cent. 

Busse    15.     per  cent. 

Arch.  d.  Pharm.   (1844),  89,  p.  30. 

"Ibid.    (1870),  191,  p.  18. 

**Ihid.,  p.  34.  ;    .    ', 


OLEORESIN  OF  CUBEB  145 

Fat.  Schmidt^^  obtained  0.511  per  cent,  of  a  semi-solid  fat 
from  fresh  cubebs,  0.408  per  cent,  from  old  cubebs.  It  is  stated 
to  be  of  ointment-like  consistence,  melting  at  30  to  32° C.  Hot 
alcohol,  ether,  carbon  disulphide,  chloroform,  benzene  and 
petroleum  ether  dissolve  it  readily.  It  is  reported  to  be  insoluble 
in  cold  alcohol. 

Cuhehin}^  Cubebin  crystallizes  from  alcohol  in  white,  odor- 
less needles  melting  at  125  to  126°C  (Schmidt), ^^  132°C 
(Mameli).^^  The  alcoholic  solution  has  a  bitter  taste.  It  is 
only  slightly  soluble  in  cold  alcohol,  quite  soluble  in  hot  alcohol, 
readily  soluble  in  ether,  chloroform,  carbon  disulphide,  glacial 
acetic  acid,  fatty  and  volatile  oils.  The  chloroformic  solution 
is  laevogyrate.  Concentrated  sulphuric  acid  dissolves  it  with  a 
purple  violet  color,  a  reaction  which  is  used  as  test  for  the 
identity  of  the  cubeb  fruit  and  the  oleoresin  prepared  therefrom. 

Cubebin  was  thought  by  Heldt^^  to  be  an  oxidation  product 
of  the  sesquiterpene  constituent  of  the  volatile  oil,  2  C15H24  -f  18 
P  =  C30H30O9  +  9  H2O.  Later  work  on  the  determination  of 
its  structure,  however,  has  shown  this  theory  to  be  untenable. 
The  following  structural  formulas  have  been  brought  forward  to 
represent  its  composition. 


CCHiCHCK&Tf 

HC|^ 

A^.„ 

"< 

^\ 

'\X. 

F.nn«lirt|it«t«tt"" 

« Ibid. 

"Monheim,  Buchner's  Repert.  f.  d.  Pharm.  (1833),  44,  p.  199;  Cassola, 
Journ.  d.  Chim.  Med.  (1834),  10,  p.  685;  Soubeiran  and  Capitaine,  Journ. 
de  Pharm.  et  de  Chim.  (1839),  25,  p.  355;  Ann.  d.  Chem.  (1840),  34,  p.  323; 
Steer,  Buchner's  Repert.  f.  d.  Pharm.  (1838),  11,  p.  88;  Ibid.  (1840),  20,  p. 
119;  Schuck,  Buchner's  n.  Repert.  f.  d.  Pharm.  (1852),  1,  p.  213;  En&el- 
hardt,  Ibid.  (1854),  3,  p.  1;  Bernatzik,  Ibid.  (1865),  14,  p.  97;  Schmidt, 
Arch.  d.  Pharm.  (1870),  191,  p.  1;  Weidel,  W^ien.  Akad.  Ber.  (1878),  74, 
p.   377. 

"  I.  c. 

"Chem.  Ztg.    (1908),  32,  p.  46. 

"Arch,   der  Pharm.    (1870),   191,  p.    23. 

*>Monatsch.  f.  Chem.   (1888),  9>  p.  323. 


146  ^U  MEZ— THE  GALENICAL  OLEORESINS 

CH 
CH  HC    ^ 

C-(Qa(OH)J-C 

CH 

(21) 
Fonnula  of  Mameli 

Cubebin  occurs  in  the  fruit  to  the  extent  of  about  2.5  per 
cent.^^ 

Ciihehic  Acid.  (Acid  Resin)  Cubebic  acid,  C13H14O71 
(Schmidt) ,f  C28H30O7H2O  (Schulze),-*  was  first  described  by 
Bernatzik.  It  is  a  white,  resinous  mass  melting  at  56  °C 
(Schmidt),  45° C  (Schulze)  and  becoming  brown  on  exposure 
to  the  air.  It  shows  only  a  weak  acid  reaction.  Alcohol,  ether, 
ammonia  and  the  caustic  alkalies  dissolve  it  readily. 

There  is  a  considerable  variation  in  the  cubebic  acid  content 
of  the  fruit  as  reported  in  the  literature.  Schmidt^^  obtained 
0.96  per  cent,  from  fresh  cubebs  and  1.16  per  cent,  from  the 
fruit  which  had  been  stored.  Bernatzik  reports  the  presence 
of  3.458  per  cent.^^ 

Resin.  The  so-called  indifferent  resin,  CisHj^Os  (Schmidt)^'' 
is  a  yellowish-brown,  pulverulent  mass  readily  soluble  in  alcohol 
and  the  caustic  alkalies,  but  only  slightly  soluble  in  ether,  chloro- 
form and  carbon  disulphide. 

The  indifferent  resin  occurs  in  the  fruit  to  the  extent  of  about 
3  per  cent,  on  the  average.^® 

Coloring  Matter,  Schmidt^^  isolated  a  brown  amorphous  sub- 
stance to  which  he  attributes  the  brown  color.  This  substance 
is  stated  to  be  soluble  in  dilute  alcohol  and  solutions  of  the  alka- 


ML    C. 

"Monheim  obtained  4.5  per  cent,  of  a  resin  resembling  piperine  which  he 
designated  cuheMn.     Buchner's  Repert.  f.  d.  Pharm.  (1833),  44.  p.  199. 

Schmidt  reports  the  presence  of  2.484  per  cent,  in  fresh  cubebs  and  2.576 
per  cent,  in  cubebs  kept  in  storage  for  some  time.     I.  c. 

MZ.   c. 

"Arch.  d.  Pharm.   (1873),  202.  p.  388. 

»I.  c. 

"Buchner's  n.  Repert.  f.  d.  Pharm.    (1865),  14,  p.  97. 

«l.  .c 

»  Schmidt  observed  the  presence  of  2.258  per  cent  .of  indifferent  resin  in 
the  fresh  fruits,  2.968  per  cent,  in  stored  fruits,  I.  c. 

Bernatzik  obtained  3.515  per  cent,  of  this  resin,   I.  c. 

»l.  c. 


OLEORESIN  OF  CTJBEB  147 

lies.  The  green  color  of  the  fatty  oil  as  observed  by  the  same 
investigator  is  stated  to  be  due  to  chlorophyll. 

Asli.  According  to  E.  Schmidt, ^^  the  ash  of  the  cubeb  fruit  is 
composed  of  the  basic  elements,  K,  Ca,  Mg,  and  Fe  in  combina- 
tion with  the  acid  radicles  CI',  SO/',  PO/",  CO3"  and  SiOa'', 
also  free  SiOs- 

Cubeb  fruits  yield  about  5.5  to  6.0  per  cent,  of  ash.^^ 

Constituents  of  Therapeutic  Importance. 

The  value  of  the  oleoresin  of  cubeb  as  a  therapeutic  agent  is 
very  probably  due  to  its  resin  content.  In  addition  to  its 
diuretic  action,  the  acid  resin  is  said  to  render  the  urine  feebly 
antiseptic  and  to  act  as  an  astringent.^  Cubebin  has  been  shown 
to  be  physiologically  inactive  passing  through  the  intestines 
unabsorbed.-  The  volatile  oil  is  stated  to  act  merely  as  a  car- 
minative^ and  its  presence  is  even  considered  by  some  to  be  un- 
desirable* owing  to  its  irritating  action. 

Physical  Properties 

Ash.  According  to  E.  Schmidt,^^  the  ash  of  the  cubeb  fruit  is 
directed  by  the  United  States  Plmrmacopoeia  has  a  grass-green 
color  when  spread  out  in  a  thin  layer  on  a  white  porcelain  sur- 
face. The  commercial  product,  however,  is  often  brownish-green 
or  brown  in  color  due  to  the  use  of  the  ripe  fruit^  in  its  manu- 
facture. In  such  cases,  the  desired  green  color  is  sometimes  im- 
parted to  the  preparation  by  the  addition  of  copper  salts.* 

Odor:  The  oleoresin  has  a  strong  aromatic  odor  like  that  of 
the  crushed  cubeb  fruit.  In  fact,  the  odor  is  so  strongly  aro- 
matic that  unevaporated  solvent  (alcohol),  even  when  present 
in  considerable  amounts,  cannot  be  detected  by  the  sense  of 
smell. 


so  Arch.  d.  Pharm.    (1870),   191,  p.  11. 

"Schmidt  obtained  only  3.36  per  cent  of  ash,  I.  c. 

Warnecke  reports  the  yield  of  ash  as  5.45  per  cent.  Pharm.  Ztg.    (1886), 
31,  p.  536. 

LaWall  and  Bradshaw  give  the  ash  content  of  two  samples  of  cubeb  as 
5.70  and  6.10  per  cent.,  respectively.     Proc.  A.  Ph.  A.   (1910),   58,  p.  751. 

^Vieth,  Med.  Klin.    (1905),  p.   1276. 

•HefCter,  Arch.  f.  Exp.  Path.  u.  Pharm.   (1895),  35,  p.  871. 

« Heydenreich,  Am.  Journ.   Pharm.    (1868),   40,  p.  42. 

*Bematzik,  Buchner's  neues  Repert.    (1865),  14,  p.   97. 
»  See  under  "Drug  used,  its  collection,  preservation,  etc." 

•B6dall   (1894). 


148 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Taste:  The  taste  is  bitter  and  somewhat  spicy,  like  that  of 
cubeb,  only  more  pronounced. 

Consistence:  The  oleoresin  is,  as  a  rule,  a  rather  thin  liquid 
when  compared  with  the  other  members  of  this  class  of  prepara- 
tions. Its  consistence,  however,  varies  to  a  considerable  extent 
owing  to  a  difference  in  the  volatile  oil  content.^  Some  of  the 
preparations  examined  in  the  laboratory  were  so  thick  that  they 
could  only  be  poured  with  difficulty. 

Solubility:  The  official  preparation  forms  clear  or  slightly 
cloudy  solutions  with  alcohol,  acetone,  ether,  chloroform,  carbon 
disulphide,  and  glacial  acetic  acid.  It  is  almost  completely 
soluble  in  petroleum  ether.  The  solubility  of  the  European 
product,  which  is  usually  prepared  with  a  mixture  consisting 
of  equal  parts  of  alcohol  and  ether,  is  about  the  same. 

Specific  gravity:  The  oleoresins  prepared  in  the  laboratory 
in  1916  showed  a  specific  gravity  of  0.99  +  at  25°  C  regardless  of 
whether  the  solvent  employed  in  extracting  the  drug  was  alcohol, 
acetone  or  ether.  The  uniformity  is  attributed  to  the  fact  that 
particular  pains  were  taken  to  evaporate  the  solvent  under  the 
same  conditions  in  each  case,  thereby  insuring  approximately 
the  same  volatile  oil  content  for  each  of  the  finished  prep- 
arations. The  variation  in  specific  gravity  due  to  a  difference 
in  volatile  oil  content  is  shown  in  the  data  given  for  the  first 
four  of  the  laboratory  preparations.  The  commercial  samples 
examined  also  show  a  variation  due  to  this  influence,  except,  in 
the  case  of  the  low  specific  gravity  observed  by  Procter,  which 
was  stated  to  be  due  to  the  presence  of  unevaporated  solvent 
(ether).     Tables  illustrating  these  points  follow: 

Table  49 — Specific  gravities  of  laboratory  preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity 

1 

1866 

1910 
1916 

Procter  

Alcohol 

At  76°  F 
0.985 

2 

Ether 

0.967 

3 

«' 

Benzin 

0  932 

1 

DuMez  &  Netzel 

Alcohol 

At  25°  C 
0  980 

2 

Acetone 

0.994 

3 

♦> 

Ether 

0  985 

1 

DuMez 

Alcohol     

1.049  (1) 
0.994 

2 

3 

•• 

Acetone 

Ether ... 

0  999 

4 

•» 

0  998 

5 

'• 

Petrol,  ether 

0  963 

*A  thick  preparation  containing  only  4.71  per  cent,  of  volatile  matter. 


See  under  "Chemistry  of  the  drug  and  the  oleoresin". 


OLEORBSIN  OF  CUBEB 


149 


Table  50SpeciJlc  gravities  of  commercial  olcoresins. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
gravity 

1  . 

1866 
1916 

At  76°  F. 
0.900  (»> 

1 

DuMez 

Lillv  &  Co 

At  Z'y°  C. 
0.968 

2 

Squibb  &  Sons 

0.969 

3 

»» 

Parke,  Davis  &  Co 

Sharp  &  Dohme 

Stearns  &  Co 

0.971 

4 

•' 

0.975 

5 

•»       ' 

1.017 

^  Contained  ether. 

Refractive  index:  The  results  obtained  in  the  laboratory  in- 
dicate that  the  refractive  index  of  the  oleoresin  should  be  about 
1.499  when  determined  at  25 °C.  The  solvent  employed  in  ex- 
tracting the  drug  appears  to  have  little  influence  on  this  con- 
stant, except  in  case  petroleum  ether  is  used,  when  it  is  slightly 
lower.  The  effect  due  to  variation  in  volatile  oil  content  is  but 
slight  as  is  shown  in  the  tables  which  follow: 

Table  51. — Refractive  indices  of  oleoresins 'pre'pared   in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractive 
index 

1 

1910 
1916 

DuMez  &  Netzel 

Alcohol  

A  cetone             

At25°C 
1.495 

2 

1.499 

3 

"      

Ether 

1.499 

1 

DuMez  

Alcohol         

1  .502  (>> 

2 

Alcohol  

1  500 

3 

" 

Acetone ,... 

'.500 

4 

!!!!.!!!!!!!!!!!!!!! 

Ether 

1.499 

5 

Petrol    ether 

1.495 

(*)  Low  in  volatile  oil  content. 


Table  52 — Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1 

1916 

DuMez 

Lilly  &  Co 

At  25°  C 
1.498 

2 

1.499 

3 

" 

Parice.  Davis  «&  Co 

1  499 

4 

"                       

1.499 

5 

" 

Stearns  &  Co 

1  501 

150 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


Chemical  Properties. 

Loss  in  weight  on  heating:  An  examination  of  the  tables 
which  follow  shows  that  the  oleoresin  usually  loses  between 
20  and  40  per  cent,  on  heating  at  100  to  110°  C,  the  variation 
being  due  to  the  difference  in  the  volatile  oil  content.  The 
relatively  small  loss  in  weight  observed  in  the  case  of  four  of 
the  laboratory  preparations  is  to  be  attributed  to  the  removal 
of  a  part,  or  the  whole,  of  the  more  volatile  constituents  of  the 
essential  oil  in  the  process  of  evaporating  the  solvent.  The  com- 
paratively great  loss  noted  for  two  of  the  commercial  samples  is 
thought  to  have  been  due  to  the  presence  of  unevaporated 
solvent.  The  results  obtained  in  the  determinations  made  in 
the  laboratory  as  well  as  those  reported  in  the  literature  are 
given  in  the  tables  which  follow : 

Table  53. — Laboratory  preparations — loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent  of 
loss  on  drying 

1  

1887 
1916 

Kremel 

Alcohol 

At  100°  C 
20.40 

1 

DuMez   

Alcohol        

At  110°  C 
23.06 

■2 

Acet/Oiie 

24  10 

3 

" 

Ether  

25.88 

4 

*'     ::. ..::.■;:::::: :::: 

Petrol   ether 

25 .  24 

5 

11.99 

4  

Xcerone 

9-96 

7 

" 

Ether  

8.81 

8 

Alcohol   

4.71 

Table  54 — Commercial  oleoresins — loss  in  weight  on  heating. 


Sample 
No. 

Date 

1893 
1.S94 
1895 
1905 

1916 

Observer 

Source 

Per  cent  of 
loss  on 
drying' 

1 

Dieterich 

At  100°  C 
32.70 

1 

31  OJ 

1 

i» 

20  90 

I 

«' 

55.91(1) 

I 

DuMez 

Sharp  &  Dohme 

At  110°  C 
30  72 

2 

31.68 

3 

Parke.  Davis  &  Co 

37  03 

4 

Lilly  &  Co 

44.21  (1) 

5 

Squibb  &  Sons 

61.96  (') 

*  Probably  contained  unevaporated  solvent    (alcohol). 


OLEORESIN   OF   CUBES 


151 


Ash  content:  The  ash  content  of  the  oleoresin  varies  with 
the  solvent  employed  in  its  preparation  as  is  shown  in  the  first 
of  the  tables  which  follow.  The  highest  values  were  obtained 
for  the  official  product,  in  the  preparation  of  which  alcohol 
was  the  solvent  used.  The  camparatively  low  ash  content  ob- 
tained for  the  commercial  samples  examined,  while  suggesting 
the  use  of  some  other  solvent  in  the  manufacture  of  these 
preparations,  is  thought  to  have  been  due  to  the  greater  amount 
of  volatile  matter  (essential  oil)  present.  Although  copper 
was  detected  in  the  ash  of  all  of  the  commercial  products,  the 
quantities  present  were  too  small  to  effect  the  value  of  this 
constant  to  any  considerable  extent.  The  following  tables 
give  the  ash  content  of  the  oleoresin  as  reported  in  the  litera- 
ture and  as  determined  in  the  laboratory: 

Tablb  55. — Ash  contents  of  oleorexins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent  of 
ash 

1 

1916 

DuMez 

Alcohol 

Acet»jne 

Ether 

0  45 

0.20 

" 

0.13 

•' 

0.07 

•• 

Alcohol 

0  48 

^ 

'• 

0  22 

" 

Fther 

0  15 

8 

'• 

Alcohol 

0  51 

Table  5G — Ash  contents  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Percent, 
of  ash 

Forelgrn  crm- 
stituents 

1893 
1894 
1895 
1897 
1905 
1916 

Dieterich  . . . 
Du Mez  ....... 

0  50 

0.52 

0.47 

0.10 

0.87 

0  21  (') 

0.40 

0  35 

0.''9  (1) 

0:37 

•' 

•» 

1 

•' 

Squibb  &  Sons 

Copper 

2 

Sharpe   &  Dohme 

" 

Lilly  &  Co 

'• 

Stearns&Co 

>> 

* Unevaporated  solvent    (alcohol)    probably  present. 


Acid  number:  The  acid  numbers  of  the  oleoresins  prepared 
in  the  laboratory  varied  from  21.8  to  26.7,  depending  on  the 
nature  of  the  solvent  employed  in  their  preparation.     The  num- 


152 


DU  MEZ— THE  GALENICAL  OLEORESINS 


/ 


ber,  26.7,  obtained  in  the  case  of  the  preparation  made  with 
alcohol  agrees  very  well  with  that  (26.2)  obtained  by  Kremel 
for  the  oleoresin  when  prepared  in  a  like  manner.  The  low  acid 
numbers  obtained  for  the  commercial  samples  are  explained 
by  the  presence  of  relatively  large  amounts  of  volatile  matter 
(generally  essential  oil,  but  unevaporated  solvent  in  two  cases) 
in  these  preparations,  which  has  the  effect  of  reducing  the  con- 
centration of  the  free  acids.  The  values  obtained  for  this 
constant  follow: 

Table  57. — Acid  numbers  of  laboratory  preparations. 


Sample 
No. 

Date 

Observer 

Solvent 

Acid  number 

1 

1887 
1916 

Kremel 

26.2 

2 

Ether  

31.2 

1 

DuMez     . 

Alcohol 

26  7 

2 

22.8 

3 

" 

Ether 

22  2 

4 

21.8 

Table  58 Acid  numbers  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Acid  number 

1. 

1916 

DuMez  

Lilly  «&  Co 

12.8(1) 

2 

SQuibb  &  Sons 

13.4(1) 

3.!..!.... 

" 

Stearns  &  Co 

14.4 

4 

" 

Parke,  Davis  &Co 

Sharp  &  Dohme 

— 

15.4 

5 

"        

18.7 

(>)  Probably  contained  unevaporated  solvent  (alcohol), 


Saponification  value:  The  saponification  values  obtained  for 
the  oleoresins  prepared  in  the  laboratory  showed  a  slight 
variation  due  to  the  nature  of  the  solvent  used  in  extracting 
the  drug  as  is  shown  in  the  first  of  the  tables  which  follow.  As 
a  rule,  however,  the  difference  in  the  volatile  oil  content  of  the 
oleoresin,  due  to  a  variation  in  the  conditions  under  which  it 
has  been  prepared,  is  thought  to  be  the  principal  factor  in- 
fluencing the  value  of  this  constant,  as  is  also  brought  out  in  the 
first  table.  In  the  examination  of  commercial  samples,  the 
presence  of  unevaporated  solvent  must  be  taken  into  considera- 


OLEOKBSIN  OF  CTJBEB 


153 


tion  in  this  connection.      The  results  obtained  in  the  determina- 
tion of  this  constant  in  the  laboratory  follow: 

Table  59 — Saponification  values  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Saponifica- 
tion value 

1 

1916 
1' 

DuMez 

Alcohol 

Acetone 

65.9 

2 

63.7 

3 

4« 

Ether 

63.4 

4 

Petrol,  ether 

67.0 

" 

Alcohol 

63.9 

2 

57.9 

3 

t» 

Ether     

59.5 

1 

105.9   (0 

1  This  preparation  contained  a  relatively  email  amount  of  volatile  matter  (principally 
essential  oil).    See  page  1056  under  "Loss  in  Weight  on  Drying". 


Table  60. — Saponification  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

1 

1916 

DuMez  

Lillv&  Co 

48.5  (0 

2 

Parice.  Davis  &  Co 

SQuibb  &  Sons 

53.3 

3.  . 

" 

49.3  {}) 

4 

i>                             •  •• 

55.0 

5 

•» 

Stearns  &  Co       

65.9 

i})  Unevaporated  solvent  (alcohol)  probably  present. 


Iodine  value:  Further  observations  are  necessary  before  a 
definite  statement  can  be  made  as  to  what  the  iodine  value  of 
this  preparation  should  be.  Determinations  made  in  the  labora- 
tory appear  to  indicate  that  it  is  influenced  largely  by  the 
volatile  oil  content  as  those  preparations  which  lost  the  greatest 
amount  on  drying  usually  gave  the  highest  values  for  this  con- 
stant. Apparent  exceptions  to  this  rule  are  to  be  found  in 
the  samples  obtained  from  Lilly  &  Company  and  Squibb  & 
Sons,  respectively.  In  these  cases,  unevaporated  solvent 
(alcohol)  is  thought  to  have  been  present,  although,  it  could 
not  be  detected  by  the  odor.  The  following  tables  show  the 
values  obtained  for  the  preparations  examined  in  the  laboratory. 


154 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  61 — Iodine  values  of  oleoresins  prepared  in  tlie  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Iodine 
value 

1916 

DuMez 

Alcohol 

126  0 

131.6 

Ether                   

138.5 

Petrol,  ether 

Alcohol 

141.8 

130.0 

113.2 

Ether 

115.6 

J 

Alcohol 

92.0 

Table  62 — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Iodine  value 

J 

1916 

DuMez 

Squibb  &  Sons 

130.61 

2 

Lilly  &  Co 

136.71 

3 

•» 

Parke,  Davis  &  Co 

Sharp  &  Dohme 

146.9 

4 

" 

147.3 

5 

»• 

Stearns  &  Co 

147.6 

^  Unevaporated  solvent  probably  present. 

Ofher  Properties. 

The  oleoresin,  upon  long  standing,  forms  a  white  deposit 
consisting  of  cubebin,  indifferent  resin,  cubebic  acid  and  thick- 
ened oil.  As  the  greater  part  (80  per  cent.)^  of  this  precipitated 
material  consists  of  the  therapeutically  inert  ciibebin,^  the 
United  States  PJiarniacopceia  directs  that  it  be  removed  before 
dispensing  the  preparation. 


Special  Qualitative  Tests. 

The  methods  which  have  been  devised  for  the  indentification 
of  this  oleoresin  or  as  a  test  for  its  quality  are  based  on  the 
fact  that  characteristic  color  changes  are  produced  when  it  is 
acted  upon  by  certain  acids.     Sulphuric,  sulphomolybdic^  and 


1  Schmidt   (1870). 

^  See  under  "Constituents  of  therapeutic  importance", 

'  Dieterich,  in  1897,  pointed  out  that  sulphomolybdic  acid  might  be  used 
in  place  of  sulphuric  acid.  The  resulting  color,  however,  was  stated  to  be 
a  cherry-red  instead  of  a  blood-red. 


OLEORBSIN  OF  CUBEB  155* 

hydrochloric^  acids  have  been  made  use  of  in  this  connection, 
the  first  mentioned  being  the  reagent  most  generally  employed. 
Attention  was  first  called  to  the  value  of  sulphuric  acid  in 
the  identification  of  this  preparation  by  Kremel  in  1887.  He,. 
however,  reported  nothing  definite,  merely  stating  that  a  car- 
mine-red color  was  produced  when  the  ''strong'*  acid  and 
oleoresin  were  mixed.  It  was  not  until  ten  years  later  (1897), 
when  the  firm  of  Dieterich  in  Helfenberg  published  their  method- 
of  procedure,  that  this  test  assumed  a  definite  form.  The  test 
as  carried  out  by  this  firm  is  typical  of  those  in  use  at  the 
present  time  and  is  as  follows: 

Upon  mixing  0.01  gram  of  the  oleoresin  with  3  to  5  drops  of  concen- 
trated sulphuric  acid,  the  mixture  should  assume  an  intense  blood-red  color." 

The  fact  that  certain  constituents  of  the  cubeb  fruit,  namely,, 
cubebin,  the  acid  resin  (cubebic  acid)  and  the  indifferent  resin, 
formed  red  colored  mixtures  with  sulphuric  acid  was  noted  by 
Schmidt  in  1870.  These  observations  have  been  confirmed  in 
this  laboratory  in  so  far  as  they  pertain  to  the  production  of  a 
red  color.  It  was  further  noted,  however,  that  the  shade  of 
red  varies  with  the  particular  constituent  under  consideration, 
the  cubebin  giving  rise  to  a  mixture  which  is  brownish-red  in 
•color,  whereas,  the  color  is  bright  red  (carmine-red)  in  the  case 
of  the  acid  or  indifferent  resin.  As  all  of  the  above  mentioned 
constituents  are  normally  present  in  the  oleoresin,  the  particular 
shade  of  red  (blood-red)  obtained  in  this  test  must  be  due  to- 
the  blending  of  the  colors  produced  by  the  action  of  the  acid' 
on  the  several  constituents,  and  cannot  be  caused  by  the  action 
of  the  acid  on  the  cubebin,  alone,  as  is  usually  reported  in  the 
literature. 

As  the  shade  of  red  obtained  will  naturally  vary  with  the 
relative  quantities  of  the  several  constituents  present,  this  test 
not  only  serves  as  a  means  of  identification,  but  is  also  of  value 
in  determining  roughly  the  quality  of  the  preparation  as  well.* 
Thus,  a  bright  red  color  obtained  by  the  action  of  the  acid  may 


1  Test  of  Gluecksmann.     See  the  following  pages. 

2  The  so-called  false  cubebs  give  a  dirty  brown  color  when  triturated  with 
concentrated  sulphuric  acid,  hence,  we  may  expect  the  oleoresin  prepared 
therefrom  to  form  a  mixture  of  a  similar  color.  See  Pharm  Ztg.  (1912)^ 
84,  p.  845. 

*  B^dall  (1894)  observed  that  the  oleoresins  possessing  a  green  color  gave 
a  more  intense  red  with  sulphuric  aeid  that  those  which  were  brown  in  color. 


156  DU  MEZ— THE  GALENICAL.  OLEORESINS 

be  taken  as  an  indication  of  the  presence  of  relatively  large 
amounts  of  the  therapeutically  active  resins,  while  a  dark  shade 
of  red  implies  that  the  cubebin  content  is  exceptionally  large 
or  that  the  resins  are  present  in  comparatively  small  amounts. 

The  test  of  Gluecksmann  (1912)  in  which  hydrochloric  acid 
is  the  reagent  made  use  of,  appears  to  be  based  on  the  presence 
of  cubebin.^     It  is  carried  out  as  follows: 

Dissolve  a  small  quantity  (a  trace)  of  the  oleoresin  in  concentrated 
acetic  acid  and  dilute  with  the  latter  until  the  solution  shows  scarcely  any 
color.  Heat  to  boiling  and  add  5  drops  of  a  35  per  cent,  solution  of 
hydrochloric  acid  to  a  5  cubic  centimeter  portion.  A  faint  yellowish-brown 
color  should  appear  immediately.  Upon  standing  quietly,  the  color  should 
change  in  2  to  4  hours  to  a  brownish-violet,  and  then  to  a  violet  blue, 
after  which  it  should  gradually   disappear. 

While  the  foregoing  may  prove  to  be  a  test  of  considerable 
worth  in  the  identification  of  the  oleoresin,  the  length  of  time 
required  for  its  completion  would  appear  to  be  a  drawback  to 
its  general  application. 

The  tests  of  this  nature  prescribed  by  the  various  phar- 
macopoeias all  involve  the  use  of  sulphuric  acid.  As  will  be- 
come apparent  in  the  following  description  of  these  methods, 
the  color  specified  differs  to  a  considerable  extent.  This  may 
"be  due,  as  already  pointed  out,  to  a  variation  in  the  relative 
quantities  of  the  reacting  constituents,  or,  as  has  been  further 
observed  in  the  laboratory,  to  the  strength  of  the  acid  employed. 
A  very  slight  dilution  with  water  will  cause  the  color  to  change 
from  red  to  purple.  The  following  are  the  tests  prescribed 
by  the  different  pharmacopoeias: 

Austrian  Pharmacopoeia  (1906)  :  The  oleoresin  should  give  a  red  color 
on  being  triturated  with  concentrated  sulphuric  acid. 

French  Pharmacopoeia  (1908) :  The  oleoresin  should  give  a  purple-red 
-color  with  concentrated  sulphuric  acid. 

Swiss  Pharmacopoeia  (1907) :  If  0.01  to  0.02  grams  of  the  oleoresin 
are  mixed  with  a  few  drops  of  concentrated  sulphuric  acid,  an  intense 
brownish-red  color  should  be  produced.  Upon  diluting  with  a  little  water, 
The  color  should  change  to  a  rose  and  upon  further  dilution,  it  should 
disappear. 

Hungarian  Pharmacopoeia    (1909) :     A   drop   of    concentrated    sulphuric 


*  This  assumption  is  made  in  view  of  the  fact  that  the  closely  related 
•compounds,  coniferyl  alcohol  and  syringenin,  give  similar  color  reactions 
'With  hydrochloric  acid.     See  Euler,  Die  Pflanzenchemie  (1908),  Vol.  I,  p.  87. 


OLEORESIN  OF  CUBES  157 

acid  added  to  a  drop  of  the  oleoresin  spread  out  in  a  thin  layer  on  a  white 
porcelain   surface   should  produce  a  blood -red  mixture. 

German  Pharmacopoeia  (1910) :  If  1  cubic  centimeter  of  a  mixture  of 
4  parts  of  concentrated  sulphuric  acid  and  1  part  of  water  is  poured  over 
1  drop  of  the  oleoresin,  a  red  color  should  be  produced.  Upon  diluting 
the  mixture  with  water  the  color  should  disappear. 

Special  Quantitative  Tests. 

Apparently  but  one  attempt  has  been  made  to  develope  a 
method  for  the  quantitative  determination  of  the  constituents 
of  therapeutic  importance  in  this  preparation,  the  same  having" 
been  made  by  Kremel  in  1887.  As  no  work  of  this  nature  was 
done  on  the  oleoresin  in  the  laboratory,  and,  as  there  is  no 
further  information  on  this  subject  in  the  literature,  a  state- 
ment cannot  be  made  as  to  the  value  of  this  method.  However,, 
as  a  suggestion  of  what  might  be  accomplished  in  this  direction, 
a  description  of  the  method  is  included  here.     It  is  as  follows : 

KremeVs  Method  for  the  Estimation  of  Cuhehic  Acid  (1887) :  Dissolve 
3  to  5  grams  of  the  oleoresin  in  4  times  the  quantity  of  alcohol  (90  per 
cent.),  filter  the  solution  and  add  alternately  to  the  filtrate  an  alcoholic 
solution  of  calcium  chloride  and  ammonia  water  until  a  distinct  cloudi- 
ness appears.  Set  the  liquid  aside  for  a  day  or  two  to  allow  the  cal- 
cium salt  of  cubebic  acid  to  crystallize.  Then,  collect  the  precipitate 
on  a  filter,  wash  successively  with  alcohol  (90  per  cent.)  and  ether,  dry 
at  lOO'C  and  weigh.  Compute  the  weight  of  the  cubebic  acid  using  the 
formula,  C    H    O  Ca,  for  the  calcium  salt. 

According  to  the  results  obtained  by  Kremel,  the  oleoresin 
prepared  with  ether  shsowed  a  cubebic  acid  content  of  2.35  per 
cent.,  while  the  same  when  prepared  with  alcohol  gave  5.75  per 
cent,  of  cubebic  acid. 

Adulterations, 

Willful  adulteration  of  this  preparation  does  not  appear  to 
be  practiced  very  extensively,  although,  the  occassional  use  of 
fixed  oils^  or  salts  of  copper^  for  this  purpose  has  been  reported 


'  Schneider  and  Suess,  Handkommentar  zum  Arzneibuch  fuer  das  deutsche 
Reich    (1902),  p.  376. 

»B6dall    (1894). 

A  trace  of  copper  is  usually  present  in  the  commercial  preparations  as  a 
result  of  the  use  of  copper  utensils  in  their  manufacture.  (See  under 
"Ash".) 


^58  ^U  MEZ— THE  GALENICAL.  OLEORESINS 

in  the  literature.  On  the  other  hand,  accidental  adulteration 
■effected  through  the  use  of  ripe  instead  of  unripe  fruits  in  the 
preparation  of  the  oleoresin  is  thought  to  be  quite  general. 
«(See  under  ''Drug  used,  its  collection,  preservation,  etc.") 

OLEORESIN  OF  GINGER 
Synonyms 

Aetherisches  Ingwerextrdkt,  Nat.  Stand.  Disp.  1884. 

Ethereal  Extract  of  Ginger,  King's  Am.  Disp.,  (1900),  p.  1336. 

Extractum  Zingiheris  aetJiereum,  Hirsh,  Univ.  P.  1902,  No.  1320. 

Extractum  Zingiberis  aethereum,  King's  Am.  Disp.  (1900),  P.  1336. 

Gingerin,  Chem.  and  Drugg.    (1913),  82,  p.  470. 

Gingerine,  Am.  Journ.  Pharm.   (1898),  70  p.  466. 

Oleoresina  Zingiberis,   U.  S.  P.  1910. 

jQl^oresine  de  Gingemhre,  U.  S.  Disp.  1907. 

Piperoide  du  Gingerribre,  B§ral,  1834. 

.Piperoid  of  Ginger,  U.  S.  Disp.  1865. 

Zingiberin,  U.  S.  Disp.  1907. 

History 

The  oleoresin  of  ginger  was  prepared  in  1834  by  Beral,  a 
^Frenchman,  but  was  apparently  first  brought  to  the  notice  of 
American  pharmacists  by  Proctor  in  1849.  It  was  intro- 
duced into  the  United  States  PJiarmacopma  in  1860  and  is  still 
official  at  the  present  time.  While  the  oleoresin  has  never 
been  officially  recognized  abroad,  a  similar  preparation  is  said 
ito  be  used  extensively  in  England  under  the  name  of  gingerin.^ 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

For  this  drug,  the  present  pharmacopoeial  definition  is  as 
follows:  "The  dried  rhizomes  oi  Zingiber  officinale  Jioscoe 
(Fam.  Zingiber aceae,)  the  outer  cortical  layers  of  which  are 
often  either  partially  or  completely  removed.  Preserve  it  in 
tightly-closed  containers,  adding  a  few  drops  of  chloroform  or 
carbon  tetrachloride,  from  time  to  time,  to  prevent  attacks  by 
insects.'^  The  official  drug  has  also  been  described  in  the 
literature  under  the  following  botanical  synonyms:  Amomum 
Zingiber  Linne,  and  Zingiber  Zingiber  (Linne)  Rusby. 


*  Gingerin   is  stated   to  be   the   extract  obtained  upon  evaporating   off   the 
•alcohol  from  the  tincture  of.  ginger.     Chem.  &  Drugg,   (1913),  82,  p.  470. 


OLEORESIN  OF  GINGER  159 

The  rhizomes  as  they  are  found  on  the  market  occur  in  a 
variety  of  forms  characteristic  of  the  source  from  which  they 
are  obtained.  In  view  of  this  fact,  the  Pharmacopoeia  recog- 
nizes six  different  commercial  varieties,  namely :  Jamaica  ginger, 
African  ginger,  Calcutta  ginger,  Calicut  ginger,  Cochin 
ginger  and  Japanese  ginger.  These  commercial  forms  differ 
to  a  considerable  extent,  not  only  through  natural  causes,  but 
also  through  a  difference  in  the  conditions  under  which  they  are 
harvested  and  prepared  for  the  market. 

As  a  rule  the  rhizomes  are  dug  after  the  stems  have  withered, 
January  or  February,  when  one  or  more  years  old.  Experience 
has  shown  the  oleoresin  content  to  be  the  greatest  at  this  period 
of  the  year.^  They  are  then  washed  in  boiling  water  to  pre- 
vent germination,  dried  rapidly  in  the  sun,  and  as  such  con- 
stitute, what  is  known  as  black,  coated,  or  unscraped  ginger. 
In  other  cases,  after  treatment  with  boiling  water,  a  part  or 
the  whole  of  the  epidermis  is  removed,  the  rhizomes  dried,  and 
bleached  with  sulphur  fumes,  chlorinated  lime,  milk  of  lime  or 
gypsum.  This  constitutes  the  so-called,  white,  uncoated, 
scraped,  race  or  hard  ginger. ^ 

In  commenting  on  the  relative  values  of  these  various  forms 
of  ginger  in  the  preparation  of  the  oleoresin,  it  should  be  stated, 
first  of  all,  that  the  yield  of  oleoresin  is  influenced  to  the  largest 
extent  by  habitat,  African  ginger  giving  the  maximum  yield.® 
Secondly,  the  extent  to  which  the  rhizomes  have  been  decorticated 
is  an  important  factor,  as  the  outer  corky  layer  contains  none 
of  the  oleoresinous  material.  These  factors  will  be  more  fully 
discussed  under  yield.  To  what  degree,  if  at  all,  the  process 
of  so-called  bleaching  effects  the  yield  or  quality  of  oleoresin 
does  not  become  apparent  from  the  literature.  It  is  thought, 
however,  that  a  heavy  coating  of  gypsum,  for  instance,  would 
tend  to  considerably  reduce  the  percentage  of  oleoresin  ob- 
tainable. 


*  Hooper,  Fharm.  Joum.   (1912),  89,  p.  391. 

'  Culbreth,  Mat.  Med.  and  Pharmacol.    (1917),  p.  130. 

» See  reference  under  "Yield  of  oleoresin". 


160 


DU  MEZ— THE  GALENICAL.  OL.EORESINS 


V.  S.  P.  Text  and  Comments  Thereon. 

The  oleoresin  of  ginger  first  became  official  in  the  Pharmaco- 
poeia of  1860.  It  has  remained  official  throughout  all  of  the? 
subsequent  editions. 

1860 

Oleoresina  Zingiberis 

Oleoresin  of  Ginger 

Take  of  ginger/  in  fine  powder,*  alcohol  until  twelve  fluidounces  ^  of 
twelve  troyounces;  filtered  liquid  have  passed.  Eecover 
Stronger  Ether ^  twelve  fluidounces;  from  this,  by  distillation  on  a  water- 
Alcohol*  a  sufficient  quantity.  bath,  nine  fluidounces  of  ether,'  and 
Put  the  ginger  into  a  cylindrical  expose  the  residue,  in  a  capsule,  until 
percolator,"  press  it  firmly,  and  pour  the  volatile  part  has  evaporated.* 
upon  it  the  stronger  ether."  When  this  Lastly  keep  the  oleoresin  in  a  well- 
has  been  absorbed  by  the  powder,  add  stopped  bottle." 


1870 


Oleoresina 

Oleoresin 

Take     of     ginger,*     in    fine    powder,* 

twelve  troyounces; 
Stronger  Ether'  twelve  fluidounces; 
Alcohol*  a  sufficient  quantity. 

Put  the  ginger  into  a  cylindrical 
percolator,  provided  with  a  stop-cock, 
and  arranged  with  a  cover  and  recep- 
tacle suitable  for  volatile  liquids,'  press 
it      firmly,     and     pour    upon   it    the 


Zingiberis 
of  Gringer 

stronger  ether.*  When  this  has  been, 
absorbed  by  the  powder,  add  alcohol 
until  twelve  fluidounces  of  liquid  have 
slowly  passed.'  Eecover  from  thia  the 
greater  part  of  the  ether  by  distilla- 
tion on  a  water-bath,'  and  expose  the 
residue,  in  a  capsule,  until  the  volatile 
part  has  evaporated.*  Lastly,  keep 
the  oleoresin  in  a  well-stopped  bottle.*" 


1880 


Oleoresina 

Oleoresin 

Ginger,*  in  No.  60  powder,*  one  hun- 
dred (100)  parts 100 

Stronger  Ether,'  a  sufficient  quantity. 
Put  the  ginger  into  a  cylindrical 
percolator,  provided  with  a  cover  and 
receptacle  suitable  for  volatile  liquids," 
press  it  firmly,  and  gradually  pour 
stronger  ether  upon  it,  until  one  hun- 
dred  and   fifty    (150)    parts    of   the 


Zingiberis 
of  Ginger 

liquid  have  slowly  passed,  or  until  the 
Ginger  is  exhausted.'  Eecover  the 
greater  part  of  the  ether  by  distilla- 
tion on  a  water-bath,'  and  expose  the 
residue,  in  a  capsule,  until  the  remain- 
ing ether  has  evaporated.' 

Keep  the  oleoresin  in  a  well-stopped 
bottle." 


OLEORBSIN  OF  GINGER 
1890 

Oleoresina  Zingiberis 
Oleoresin  of  Ginger 

Ginger/  in  No.  60  powder,^  five  hun-  portions,  until  the  drug  is  exhausted.* 

dred  grammes 500  Gm.  Eeeover  the  greater  part  of  the  ether 

Ether,^  a  sufficient  quantity.  from  the  percolate  by  distillation  on 
Put  the  ginger  into  a  cylindrical  a  water-bath,»  and,  having  transferred 
glass  percolator,  provided  with  a  stop-  the  residue  to  a  capsule,  allow  the  re- 
cock,  and  arranged  with  cover  and  maining  ether  to  evaporate  spontaa- 
receptacle  suitable  for  volatile  liquids."  eously." 

Press  the  drug  firmly,  and  percolate  Keep   the  oleoresin  in   a  well-stop- 

slowly  with  ether,  added  in  successive  pered  bottle.^" 

1900  >; 

Oleoresina  Zingiberis  ' 

Oleoresin  of  Ginger 

Ginger,*  in  No.  60  powder,'  five  hun-  is   exhausted.^       Eeeover   the   greater 

dred  grammes 500  Gm.  part  of  the  acetone  from  the  percolate 

Acetone,^  a  sufficient  quantity.  by  distillation  on  a  water-bath,«  and, 

Introduce  the  ginger  into  a  cylindri-  having  transferred  the  residue  to  a 
cal  glass  percolator,  provided  with  a  dish,  allow  the  remaining  acetone  to* 
stop-cock,  and  arranged  with  a  cover  evaporate  spontaneously  in  a  warmi 
and  a  receptacle  suitable  for  volatile  place.*  Keep  the  oleoresin  in  a  well- 
liquids."  Pack  the  powder  firmly,  and  stoppered  bottle." 
percolate  slowly  with  acetone,  added  Average  dose. — 0.030  Gm.  =  3(r 
in  successive  portions,  until  the  ginger  milligrammes   (%  grain.) 

1910 

Oleoresina  Zingiberis 

Oleoresin  of  Ginger 

Oleores.  Zingib. 

Ginger,*  in  No.  60  powder,''  five  hun-  hausted.'     Eeeover  the   greater    part 

dred  grammes 500  Gm.  of  the  ether  from  the  percolate   bj 

Ether,'  a  sufficient  quantity.  distillation,  on  a  water-bath,*  and, 
Place  the  ginger  in  a  cylindrical  having  transferred  the  residue  to  a 
glass  percolator,  provided  with  a  stop-  dish,  allow  the  remaining  ether  to 
cock  and  arranged  with  cover  and  a  evaporate  spontaneously  in  a  warm 
receptacle  suitable  for  volatile  liquids."  place.*  Keep  the  oleoresin  in  a  well- 
Pack  the  powder   firmly,   and  perco-  stopped  bottle.** 

late  slowly  with,  ether,  added  in  sue-  Average    dose. — Metric,  0.03  Gm.^ 

eessive  portions,  until  the  drug  is  ex-  Apothecaries,  %  grain. 


162  ^^  MEZ— THE  GALENICAL.  OL.EORESINS 

1)  For  a  description  of  the  different  commercial  varieties  of 
the  official  drug,  see  page  1065  under  ''Drug  used,  its  collection, 
preservation,  etc." 

2)  As  starch,  in  the  shape  of  fine  granules,  constitutes  about 
20  per  cent,  of  the  ginger  rhizome,  the  latter  can  only  be  ob- 
tained in  the  form  of  a  uniformly  fine  powder  by  reducing 
the  other  tissues  to  a  corresponding  degree  of  fineness.  It  is  for 
this  reason  and  for'  the  purpose  of  insuring  the  complete 
breaking  up  of  all  of  the  small  resin  cells  that  the  Pharma- 
•copoeia  directs  that  the  drug  be  reduced  to  a  No.  60  powder. 

3-4)  Ether  is  the  solvent  which  appears  to  be  best  adapted  to 
the  preparation  of  this  oleoresin  in  that  it  completely  extracts 
the  pungent  principles  from  the  drug  and  yields  a  product 
containing  a  minimum  amount  of  undesirable  extractive  mat- 
ter. According  to  Garnett  and  Grier  (1909)  acetone,  which 
"was  directed  to  be  used  by  the  Pharmacopoeia  of  1900,  does 
not  completely  exhaust  ginger,  even  when  a  Soxlet's  appara- 
tus is  used.  It  is,  therefore,  fortunate  that  the  present  Phar- 
macopoeia again  specifies  that  ether  be  used  for  this  purpose. 

In  the  earlier  editions  of  the  Pharmacopoeia  (editions  of 
1860  and  1870),  alcohol  was  directed  to  be  used  as  a  "follow 
lip"  solvent  to  replace  the  ether  with  which  percolation  was 
begun.  This  procedure  was  abandoned  in  1880  for  reasons 
which  will  be  discussed  later. 

5)  Since  1870,  the  Pharmacopoeia  has  directed  that  percola- 
tion be  carried  out  in  a  special  form  of  percolater  adapted  to 
the  use  of  volatile  liquids.  For  a  description  of  such  forms, 
see  Part  I  under  ''Apparatus  used." 

6-7)  The  method  of  extracting  the  drug  as  outlined  in  the 
earlier  editions  of  the  Pharmacopoeia,  the  editions  of  1860  and 
1870,  was  essentially  the  same  as  suggested  by  Beral  in  1834. 
See  Part  I,  page  929.  From' a  practical  standpoint,  this  method 
possessed  distinct  advantages,  especially  at  the  time  when  it 
was  adopted,  in  that  a  considerable  saving  in  the  cost  of  the 
preparation  of  the  oleoresin  was  effected  through  the  use  of 
alcohol  as  a  "follow  up"  solvent  for  replacing  the  relatively 
expensive  ether.  The  method,  however,  was  not  entirely  sat- 
isfactory as  the  finished  product  contained  a  considerable 
amount  of  undesirable  extractive  matter  owing  to  the  greater 
•solvent  properties  of  the  alcohol.    Another  disadvantage  lay 


OLEORESIN  OF  GINGER  153 

in  the  fact  that  a  relatively  large  amount  of  volatile  oil  was 
lost  in  the  removal  of  the  solvent. 

The  present  edition  of  the  Pharmacopoeia  directs  that  the 
drug  be  completely  exhausted  by  simple  percolation  with 
ether.  Here,  as  in  the  case  of  the  oleoresin  of  capsicum,  the 
extraction  of  the  drug  with  the  aid  of  some  form  of  continu- 
ous extraction  apparatus  would  effect  a  considerable  saving 
in  solvent  and  without  injury  to  the  finished  product. 

8-9)  With  respect  to  the  removal  of  the  solvent  from  the  per- 
colate, the  present  edition  of  the  Pharmacopoeia  directs  that 
this  be  accomplished  in  greater  part  by  distillation  on  a  water 
bath  and  that  the  remainder  be  allowed  to  evaporate  spon- 
taneously in  a  warm  place,  a  procedure  similar  to  that  de- 
scribed in  the  earlier  editions.  For  reasons,  identical  with 
those  given  in  the  comments  on  the  oleoresin  of  cubeb  (see 
page  1045),  it  is  thought  that  the  pharmacopoeial  directions 
should  include  specific  statements  with  reference  to  the 
amount  of  solvent  to  be  recovered  by  distillation  and  the  tem- 
perature at  which  the  remainder  is  to  be  removed  in  order  to 
insure  greater  uniformity  in  the  product  obtained. 

10)  Upon  exposure  to  the  air,  a  portion  of  the  volatile  oil  con- 
tained in  the  oleoresin  is  altered  (resinified)  or  lost  through 
evaporation.  The  preparation  should,  therefore,  be  kept  in 
well-stoppered  bottles. 


Yield 

With  respect  to  the  solvents,  alcohol  (95  per  cent.),  acetone 
and  ether,  the  yield  of  oleoresin,  in  the  case  of  ginger,  varies  in 
magnitude  in  the  order  in  which  the  solvents  are  mentioned. 
For  these  menstrua,  a  minimum  yield  of  2.57  per  cent  has  been 
reported  while  the  maximum  yield  has  been  stated  to  be  as  high 
as  11.1  per  cent.  .  When  petroleum  ether  is  the  solvent  used, 
the  yield  is  much  lower,  being  only  about  one-half  that  obtained 
in  the  preceding  cases.  In  this  connection,  the  source  of  the 
rhizomes  is  a  factor  of  first  importance.  Thus,  it  has  been 
found  that  Jamaica  ginger  usually  gives  the  smallest  yield  and 
African  ginger  the  highest,  while  Cochin  ginger  occupies  an 
intermediate  position  in  this  respect.  These  facts  will  be 
brought  out  more  clearly  in  the  tables  which  follow. 


-^Q^  DU  MEZ— THE  GALENICAL.  OLEORESINS 

The  yield  of  oleoresin  is  further  influenced  by  the  degree  to 
which  the  rhizomes  have  been  deprived  of  the  outer  corky  layer, 
and,  in  the  case  of  bleaching,  to  the  manner  in  which  the  latter 
was  accomplished.  "With  respect  to  this  statement,  the  yield, 
in  the  case  of  the  unbleached  ginger,  will  be  the  greatest  when 
decortication  is  complete.  When  the  rhizomes  have  been 
bleached,  in  addition  to  being  partially  or  wholly  decorticated, 
the  influence  of  the  latter,  may  be  diminished,  in  part  at  least, 
by  the  process  employed  in  accomplishing  the  f onner.  Thus,  if 
gypsum  or  lime  have  been  used  for  this  purpose,  the  weight  of 
the  insoluble  material  in  the  rhizomes  will  be  considerably  in- 
creased, which  will  have  the  effect  of  reducing  the  percentage 
yield  of  oleoresin.  These  points  are  also  brought  out  in  the 
tables  which  follow. 


OLEORESIN  OF  GINGER 


165 


Table  63.  —  Yield  of  oleoreain  as  reported  in  the  literature. 


Date 
1834 

Observer 

Yield  of  oleoresin  to— 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

B6ral 

Per  ct. 

Per  ct. 

Per  ct. 

5.20 
3.29 
4.96 
8.06 
3.58 

Per  cent. 

1879 

.Tamaica  ginger. 
Cochin         *' 

.Tones 

1886 

3.38 
fAlco- 
1  hoi 
|(  sp. 
1     gr. 
1   0.82) 
\  5.00 
1   4.80 
1 
6.65 
6  57 
6.17 
I  7.00 

1888 

Siggnis 

Jamaica  ginger,  unbleached. 
'*             *'     ,  bleached 

Trimble 

(limed) 
East  Indian  ginger. 

African  ginger. 

18S8 

3.97 

i      Benzin 
1           2.48 
3      Benzin 
1           2.50 

1891 

Rlegel 

5.00 
8.00 

Jamaica  ginger,  unbleached. 
East  Indian  ginger,   epidermis 

Sherrard 

8.00 

3.85 
4.72 
5.20 
5.40 

1892 

removed. 

Beringer 

1892 

5.57 

1893 

Dyer  and  Gilbard 
Davis 

3.00  to 
5.20 

4.30  to 
4.84 

5.75  to 
6.27 

5.50 
5.00 
4.33 
6.33 

2.57  to 
6.41 

2.97  to 
4.60 

Upon    subsequent     extraction 

1895 

with  alcohol  0.80  to  1.50  per 
cent,    of    material    was    ob- 
tained. 
Jamaica  ginger. 

African       " 

1896 

I      Methyl 
\      alcohol 
\        6.50 

1S97 

Glass  and  Thresh 

.Jamaica  ginger. 

r  Alco- 
hol 
(90 
per 

cent.) 

3.94to 

5.61 

3.41to 
,5.67 

4.91to 

6.74 

5.4110 

6.51 

5.14to 

6.61 

5.14to 
16.47 



Cochin 

African 

IdOl 

Jamaica  ginger,  whole. 

Ballard 

•Jamaica  ginger,  ground. 



Cochin  ginger,  whole. 

Cochin  ginger,  ground. 

African  ginger,  whole. 

African  ginger,  ground. 

1903 

3.75 
6.33 

fEth'r 

(Sp. 

gr. 

-!  0.717) 
1   4.76 
1   6  04 
111.09 

Tahiti  ginger. 

Southall  Bros, 
&  Barclay 

Ivory  Coast  ginger. 

1903 

r  Alco- 
hol 
(90 

J    per 

Icent) 
4  35 
4.57 

I  9.93 

Jamaica  ginger. 

Cochin 

African 

166  I^U  MEZ— THE  GALENICAL  OLEORESINS 

Table  63. — Yield  of  oleoresin  as  reported  in  the  literature — Continued. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1908 

Vanderkleed .... 

Per  ct. 

Per  ct. 

Per  ct. 

Per  cent 

I  Solvent  (?) 
\        5.58 
/        9.55 
j   Solvent(?) 
1   3.14  to  6.91 

8.20 
9.03 

Reported  as  yield  of  oleoresin. 

1909 

Vanderkleed .... 

Represents  tlie   yield  from    16 

1909 

Vanderkleed  .... 

samples  of  Jamaica  ginger. 
Reported  as  oleoresin. 

Vanderkleed .... 

1909 

Patch 

3.70  to 
6.20 

1910 

Vanderkleed .... 

r  Solvent(?) 
5.63 
6.31 
10.12 

3.40  to  6.60 

j   7.12  to  9.48 

1   3.44  to  6.64 

1  6.85  to  11.10 

I 

\  Jamaica  ginger.   Reported  as 
(      yield  of  oleoresin. 

Vanderkleed 

African    ginger.    Reported  as 

1911 

yield  of  oleoresin. 
Jamaica  ginger.    Reported    as 

Vanderkleed.... 

yield  of  oleoresin. 
African    ginger,    Repoi'ted    as 

1912 

yield  of  oleoresin. 

Patch 

yield  of  oleoresin. 
African   ginger.      Reported  as 

1912 

3.30  to 
6.00 
6.40 

8.30 

4.23 

yield  of  oleoresin. 
Jamaica  ginger. 

1912 

Hooper 

Young  rhizomes  harvested  in 

Patch 

December. 
Rhizomes  harvested    in    Feb- 

1913 

ruary  . 
Average  yield  of  9  samples  of 

1913 

Vanderkleed 

j  SolventC?) 
1   3.10  to  5.75 

S  Solvent(?) 
1  6.85  to  9.92 

J  SolventC?) 
1  2.81  to  5.24 

ginger. 
Reported  as  yield  of  oleoresin. 

1913 

Vanderkleed  . . . . 

Results  obtained  in  extract- 
ing  37   samples  of    Jamaica 
ginger. 

Results  obtained  in  extracting 

1913 

Engelhard  t 

17  samples  of  African  ginger. 
Results  obtained  in  extracting 

1914 

Rlppetoe 

4.98 
5.50 
6.20 
6.23 



2.79 
4  97 
5.31 
5.45 

8  samples  of  Jamaica  ginger. 
Jamaica  ginger. 

Vanderkleed  . . . . 

African  ginger. 

1914 

S  Solvent(?) 
1        5.06 

9.00 

3.93 
7.99 
8.90 

Average  yield  of  3  samples  of 

Vanderkleed 

Jamaica  ginger. 
Average  yield  of  3  samples  of 

1915 

African  ginger. 
Yield  of  Jamaica  ginger. 

"    African  ginger. 



OLEORESIN  OF  GINGER 


167 


Table  6L  — Yield  of  oleoredn  as  obtained  in  the  laboratory. 


Yield  of  oleoresin 

Date 

Observer 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1909 

DuMez  &  Arnold 

DuMez  &  Netzel. 
DuMez   

Per  ct. 
6.60 

6.33 
6.28 

Per  ct. 

5.62 
5.49 

Per  ct. 
5.30 

5.00 
4.92 

Per  cent 

Represents  yield  using  a  Soxh- 
lei's  extraction  app.^  except- 

1910 
1916 

Henzin 

2.57 

Petrol,  ether 
3.15 

in  the  case  of  alcohol. (^) 

Represents  yield  usinj?  a  Soxh- 
let's  extraction  app. .    except 
in  the  case  of  alcohol. 

Represents  yield  using  a  Soxh-^ 
let's  extraction  app.,  except 
in  the  case  of  alcohol. 

1  Jamaica  ginger  was  the  variety  of  the  drug  used  in  all  cases.  When 
alcohol  was  the  solvent  employed,  the  process  of  extraction  was  that  of 
simple  percolation. 


Chemistry  of  the  Drug  and  Oleoresin. 

Tabulation  of  Constituents, 

The  chemistry  of  the  constituents  of  ginger  is  still  incomplete 
in  many  details,  although,  it  has  been  the  subject  of  a  number  of 
investigations.^  In  the  light  of  our  present  knowledge,  the  fol- 
lowing may  be  said  to  comprise  the  constituents  ol  importance 
to  the  pharmacist:  volatile  oil,  gingerol,  resins,  fat,  wax,  gum, 
sugar,  starch  and  inorganic  matter.  Thresh^  has  identified  the 
following  in  the  oleoresin  prepared  by  extracting  the  rhizomes 
with  ether : 


Volatile  Oil 
Gingerol 


Eesin 
Fat 


Wax 

Ash 


Occurrence  and  Description  of  Individual  Constituents. 

Volatile  Oil.^    The  volatile  oil  or  so-called  essence  of  ginger 
is  described  by  Thresh*  as  being  a  pale  straw  colored  limpid 


»Morin,  Journ.  de  Pharm.  et  de  Chim.  (1823),  9,  p.  25$;  Thresh,  Pharm. 
Journ.  (1879),  39,  p.  171;  Jones,  Chem.  &  Drugg.  (1886),  28,  p.  413;  Gane, 
Pharm.  Journ.  (1892),  51,  p.  802;  Balland,  Journ.  Pharm.  Chim.  (1903),  18, 
p.  248;  Reich,  Zeitschr.  Unters.  Nahr.  u.  Genussm.      (1907),  14,  p.  549. 

M.  c. 

"The  description  of  the  volatile  oil  as  given  above  is  for  the  product  ob- 
tained from  the  rhizomes  by  steam  distillation.  The  oil  as  it  exists  in  the 
oleoresin  prepared  from  the  rhizomes  by  extraction  with  a  solvent  will  un- 
doubtedly differ  somewhat. 

*Pharm.  Journ.  (1881),  41,  p.  198;  Tear-Book  of  Pharm.   (1881).  18.  p.  39S. 


168  ^^  MEZ— THE  GALENICAL  OLEORESINS 

fluid  with  a  somewhat  camphoraceous  odor  and  an  aromatic,  but 
not  a  pungent  taste.  It  is  laevogyrate  (-25  to  50°)  and  has  a 
specific  gravity  of  0.875  to  0.886.  It  is  soluble  in  strong  alcohol, 
petroleum  ether,  carbon  disulphide,  benzene,  turpentine  and 
glacial  acetic  acid.  The  principal  constituent  of  the  oil,  a 
sesquiterpene,  gingerene  or  zingiberene,  (C15H24)  was  first 
definitely  described  by  von  Soden  and  Rojahn^  in  1900.  Accord- 
ing to  Semmler  and  Becker,^  it  is  a  monocyclic  butadiene  having 
the  -following  structure : 


CH          CH. 

H,C 

f  y  Y 

H.C 

k  A"  A"' 

¥  I 

CH, 

The  former  investigators  also  identified  d-camphene  and  phellan- 
drene^  in  the  lower  boiling  fractions.  In  addition  to  these  hy- 
drocarbons, Schimmel  &  Company®  have  reported  the  presence 
of  citral,  cineol,  borneol  and  probably  geraniol,  and  Dodge^  the 
presence  of  an  aldehyde  of  the  probable  formula,  n-CglligCHO. 
The  volatile  oil  has  been  found  to  be  present  in  the  rhizomes 
in  varying  quantities  depending  on  their  age  before  harvesting, 
the  methods  of  curing   and   their    geographical    source.^*'     Ac- 


•Pharm.  Ztgr.   (1900),   45.  p.  414. 

•Ber.  d.  deutsch.  chem.  Gesell.    (1913),  46,  p.  1814. 

T  Schimmel  &  Co.  Semi-Ann.  Rep.   (1905),  II,  p.  38. 

'  Phellandrene  and  d-caniphene  were  identified  in  the  oil  by  Bertram  and 
Walbaum  in  1894.    Journ.  f.  prakt.  Chem.  (1894),  49,  p.  18. 

•Chem.  Abs.  (1912),  6,  3,  p.  2976;  Orlg.  Com.  8th  Intern.  Congr.  Appl. 
Chem,  6  p.  77. 

*»  Gane  reports  the  presence  of  volatile  oil  in  ginger  as  follows :  Jamaica 
0.64  per  cent.,  Cochin  1.35  per  cent.,  African  1.615  per  cent,  Fijian  1.45  per 
cent.     Pharm.  Journ.    (1892),  51,  p.   802. 

Thresh  obtained  0.75  per  cent,  of  oil  from  Jamaica  ginger,  1.35  per  cent, 
from  Cochin  and  1.61  per  cent,  from  African.  Pharm.  Journ.  (1879),  39, 
p.l.   191. 

Haensel  states  that  he  obtained  only  1.072  per  cent,  of  volatile  oil  from. 
Jamaica  ginger,  whereas  other  sorts  yielded  from  2  to  3  per  cent.  Pharm. 
Ztg.   (1903),  48,  p.  58. 

Bennet  found  0.20  to  0.90  per  cent,  of  oil  in  Jamaica  ginger,  Pharm.  Journ. 
(1901),  66,  p.  522. 

Reich  gives  the  following  as  the  volatile  oil   content   of  various   sorts  of 


OLEORESIN  OF  GINGER  169 

cording  to  Cripps  and  Brown  a  ''good  ginger"  will  yield  from 
2.24  to  3.48  per  cent.^^ 

Gingerol.  Gingerol  or  zingiberoP^  is  the  constituent  or  mix- 
ture of  constituents  to  which  ginger  is  said  to  owe  its  pungency. 
It  is  a  colorless,  odorless,  viscid  fluid  possessing  an  extreme 
pungency.  Its  exact  composition  has  not  been  determined,  the 
most  recent  investigations  indicating  that  it  is  a  mixture  of 
phenols.^^  It  is  readily  soluble  in  strong  alcohol,  carbon  disul- 
phide,  benzol  and  oil  of  turpentine,  but  only  slightly  soluble  in 
petroleum  ether. 

Gingerol  is  present  in  the  rhizomes  in  amounts  varying  from 
0.6  to  1.82  per  cent.^* 

Resins.  The  resins  of  ginger  have  been  isolated  and  described ; 
by  Thresh.^ ^  This  investigator  recognizes  four  individuals  with 
respect  to  their  physical  properties  and  their  behavior  toward 
acids  and  alkalies,  viz :  a  neutral  resin,  an  a-resin,  a  jS-resin  and 
a  y-resin. 

The  neutral  resin  is  stated  to  be  a  black,  pitch-like  substance; 
soluble  in  ether,  alcohol,  benzene  and  oil  of  turpentine,  but  in- 
soluble in  petroleum  ether  and  carbon  disulphide. 

The  a-resin  is  a  soft,  but  brittle  substance  soluble  in  ether> 
and  alcohol,  but  insoluble  in  the  remainder  of  the  above  men- 
tioned solvents. 

The  /8-resin  is  also  soft  and  brittle,  but  is  soluble  in  all  of  the 
above  solvents. 

The  y-resin  is  firmer  in  consistence  and  is  soluble  in  ether, 
alcohol  and  petroleum  ether. 

The  total  resin  content  of  the  rhizomes  varies  to  a  considerable  • 


ginger:     Cochin  1.38  per  cent.,  Japan  1.38   per  cent,  Bengal  1.6  per  cent», 
African    2.54    per    cent.     Zeitschr.    Unters.    Nahr.    u.    Genussm.     (1907),    1^, 
p.   549. 

"Analyst   (1909),  34,  p.  519. 

"The  term  gingerol  was  first  used  by  Thresh  in  1884  to  designate  the 
pungent  principle  of  ginger.     Year-Book  of  Pharm.   (1884),  21,  p.  516. 

Zingiberol  is  evidently  a  modification  of  the  above,  the  idea  being  to  bring 
the  nomenclature  in  closer  conformity  with  the  name  of  the  botanical  source — 
Zingiheris  officinale  Roscoe. 

"Garnet  and  Grier,  Year-Book  of  Fharm.    (1907),   44,  p.  441, 

"  Thresh  obtained  gingerol  in  the  following  quantities :  Jamaica  ginger 
0.66  per  cent..  Cochin  0.60  per  cent.,  African  1.45  per  cent.  Pharm.  Joum. 
(1879),   39,   p.  193. 

Gane  reports  the  presence  of  the  following  percentages:  Jamaica  0.84  per^ 
cent.,  Cochin  0.60  per  cent.,  African  1.45  per  cent.,  Fijian  1.82  per  cent. 
Pharm.  Joum.   (1892),   51,  p.  802. 

"Pharm.  Journ.   (1879),  39,  p.  193. 


X70  ^U  MEZ— THE  GALENICAL  OLEORESINS 

extent  and  appears  to  depend  principally  on  their  geographical 
source.  The  minimum  yield  (1.18  per  cent.)  has  been  obtained 
from  Jamaica  ginger,  the  maximum  yield  (4.47  per  cent.)  from 
the  Fijian  rhizome.^^ 

Fat  and  Wax.  Little  or  no  work  has  been  done  toward  de- 
termining the  composition  of  the  fat  or  wax  in  ginger.  The 
two  substances,  combined,  are  stated  to  constitute  0.70  to  1.225 
per  cent,  of  the  rhizome.^'^. 

Ash.  The  qualitative  examination  of  the  ash  of  ginger  has 
been  undertaken  by  Thresh,^^  who  reports  the  presence  of  the 
basic  elements :  K,  Ca,  Mg,  Mn,^^  and  Fe  combined  with  H2CO3 
and  H3PO4.  The  ash  of  African  ginger  is  stated  to  contain  the 
largest  amount  of  manganese. 

The  ash  content^^  of  the  whole  rhizome  appears  to  be  in- 
fluenced but  little  by  the  locality  from  which  obtained,  3.0  to5.5 
per  cent,  being  conservative  limits  for  the  usual  commercial  var- 
ieties. Peeling^^  appears  to  decrease  the  amount  of  ash  while 
bleaching^-  (liming)  increases  it. 

Constituents  of  Therapeutic  Importance. 

The  physiological  action  of  the  oleoresin  of  ginger  was  at  one 
time  thought  to  be  due  to  the  resin  content,  but  the  work  of 
Thresh^  has  shown  the  pungency  to  be  the  property  of  the 
phenolic  constituents  known  collectively  as  gingerol.     The  car- 


"  Thresh  reports  the  total  resin  content  of  g-inger  as  follows :  Jamaica  1.18 
per  cent,  Cochin  1.815  per  cent.,  African  3.775  per  cent.,  Pliarm.  Journ, 
(1879),  39,  p.  173. 

Gane  noted  the  presence  of  the  following  percentages :  Jamaica  g-inger  1.76 
per  cent..  Cochin  1.815  per  cent.,  African  3.775  per  cent.,  Fijian  4.475  per 
c^nt.     Pharm.  Journ.  (1892),  51,  p.  802. 

"  The  combined  fat  and  wax  present  in  g-inger  is  stated  by  Thresh  to  be 
as  follows:  Jamaica  0.70  per  cent.,  Cochin  1.205  per  cent.,  African  1.225  per 
■cent.  I.  c. 

Gane  found  the  following  amounts:  Jamaica  ginger  0.92  per  cent.,  Cochin 
1.20  per  cent.,  African  1.225  per  cent.,  Bengal  0.86  per  cent.,  L.  C. 

"Pharm.  Journ.   (1879),  29  pp.  174  and  193. 

"See  also  Flueckiger,  Ihid.   (1872),  32,  p.  208. 

*>  C.  Richardson.  Bull.  13,  Dept  Agr.  Washing-ton,  1887;  Gane,  Pharm. 
Journ.  (1892),  51,  p.  802;  Liverseeg-e,  Vierteljahresschr.  Nahrungs-u.  Genussm. 
(1896),  11,  p.  353;  Glass,  Pharm.  Journ.  (1897),  58,  p.  245;  Bennet,  Ibid. 
(1901,  66.   p.   522. 

»Winton,  Ogden  and  Mitchell  obtained  3.66  to  4.06  per  cent,  of  ash  for  un- 
peeled  and  unbleached  Cochin  ginger,  3.36  per  cent,  for  the  same  when  peeled 
and  bleached.     Rep.  Conn.  Agr.  Exp.  Sta.    (1898),  p.  202;    (1899),  p.   102. 

22  Davis  reports  5.20  per  cent,  of  ash  for  unbleached  Jamaica  ginger,  6.  55 
per  cent,  for  the  bleached.     Fharm.  Journ.    (1895),  54,  p.  472. 

» Tear-Book  of  Pharm.   (1884),  21,  p.  516. 


OLEORESIN  OF  GINGER 


171 


minative  action  of  the  preparation  must  also  be  attributed  in 
part  to  the  volatile  oil  contained  therein. 

Physical  Properties. 

Color:  The  oleoresins  examined  in  the  laboratory  were  ob- 
served to  be  rather  dark  brown  in  color  when  spread  out  in  thin 
layers  on  a  white  porcelain  surface.  This  property,  however, 
is  reported  to  vary  somewhat  with  the  variety  and  condition  of 
the  ginger  used  in  making  the  preparation.  When  African 
ginger  is  employed,  the  oleoresin  is  stated  to  be  dark  brown  in 
color,  whereas,  uncoated  Jamaica  ginger  is  said  to  yield  a 
preparation  comparatively  light  in  color.^ 

Odor:  The  oleoresin,  when  prepared  according  to  the  official 
process,  has  the  full  aroma  of  ginger,  the  quality  of  which  is 
stated  to  be  influenced  largely  by  the  variety  of  ginger  used.^ 

Taste:  The  preparation  has  the  sharp  pungency  and  flavor 
of  ginger.  This  property,  like  the  odor,  is  stated  to  vary  with 
the  variety  of  ginger  used,  Jamaica  ginger  yielding  the  product 
with  the  best  flavor.^ 

Consistence:  The  oleoresin  is  a  thick  liquid,  being  of  about 
the  consistence  of  molasses,  as  a  rule,  but  varying  somewhat 
with  the  variety  of  the  ginger  used  in  its  preparation.  The 
fluidity  is  said  to  be  the  greatest  when  prepared  from  Jamaica 
ginger  and  the  least  when  made  from  the  African  variety.'* 

Solubility:  The  oleoresin  is  soluble  in  absolute  alcohol,  ace- 
tone, ether,  chloroform,  and  glacial  acetic  acid.  It  is  partially 
soluble  in  petroleum  ether,  the  extent  of  its  solubility  depend- 
ing on  the  solvent  used  in  its  preparation  as  is  shown  in  the  fol- 
lowing table: 

Table  65 — Solubility  of  the  oleoresin  in  petroleum  ether. 


9ol<rent  used  in  preparing  the  oleoresin. 

Alcohol 

Acetone 

Ether 

Per  cent,  of  oleoresin  soluble  in  petrol,  ether.. 

45.55 

49.59 

69.44 

iParrish.  Treatise  on  Pharmacy,   (1867),  p.   233. 
"Idris   (1898). 
'Idris   (1898). 
*Idris   (1898). 


172 


DU  MEZ— THE  GALENICAL,  OLEORESINS 


As  will  be  noticed  this  difference  in  solubility  is  quite  pro- 
nounced and  it  should,  therefore,  serve  as  a  ready  means  of 
identifying  the  solvent  used  in  the  manufacture  of  the  prepara- 
tion. 

Specific  gravity:  At  25° C  a  specific  gravity  of  1.020  to  1.036 
was  found  for  this  oleoresin  when  acetone  or  ether  were  em- 
ployed in  its  preparation.  This  constant  was  observed  to  be 
slightly  higher  when  alcohol  was  used  as  a  menstruum  and  con- 
siderably lower  (less  than  1.000)  when  petroleum  ether  was  em- 
ployed. In  the  case  of  the  commercial  samples  examined,  a  low 
specific  gravity  is  to  be  attributed  to  the  presence  of  unevapor- 
ated  solvent  in  one  instance,  and  in  the  other,  it  is  thought  to  be 
due  to  an  abnormally  darge  volatile  oil  content.  The  data  ob- 
tained in  the  examination  of  laboratory  and  commercial  samples 
are  given  in  the  tables  which  follow. 

Table  66 — Specific  gravities  of  oleoresins  prepared  in  the  laboratory, 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity* 

1 

1916 

DuMez 

Alcohol 

At  25°  C 
1.041 

2 

Acetone  . .  .. 

1  030 

3 

1  033 

4 

•« 



1.036 

5 

•• 

Ether . 

1  020 

6 

Petrol,  ether 

0  990 

Table  ©7 — Specific  gravities  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
gravity 

1916 

DuMez. 

Squibb  &  Sons. 

At  25°  C 
0  997  1 

2 

1.014 

3 

•' 

Lilly  &  Co.. 

1  024 

1  Contained  ether. 


Refractive  index:  A  refractive  index  of  about  1.517  at  25 °C 
was  observed  for  the  preparations  made  in  the  laboratory  with 
acetone  or  ether.  When  alcohol  was  employed  in  extracting  the 
drug,  the  resulting  product  was  found  to  have  a  slightly  higher 
refractive  index,  while  petroleum  ether  yielded  an  oleoresin  in 


OLEORESIN  OF  GINGER 


173 


which  this  constant  was  observed  to  be  considerably  lower.  The 
low  refractive  index  found  for  two  of  the  commercial  samples 
was  very  likely  due  to  the  fact  that  they  contained  twice  as 
much  volatile  matter  (principally  essential  oil)  as  the  laboratory 
preparations.  The  effect  of  this  influence,  together  with  that 
produced  by  the  presence  of  unevaporated  solvent,  is  brought 
out  in  the  following:  tables: 


Table  68. — Refractive  indices  of  the  oleoresins  prepared  in  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractive 
index 

1, 

1916 

DuMez   

Alcohol 

Acetone 

At  25°  C 
1  520 

2 

1.517 

3 

1.517 

4 

Ether...!..!!..'.!...!..!!. 

1.518 

5 

.4                                                                        / 

1.517 

6 

Petrol,  ether 

1  501 

Table  69 Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1 

1916 

DuMez   

At  25°  0 
1,501' 

3 

Sharp  &  Dohme          

1.505 

2 

■    ■ 

Lilly  &  Co        

1.512 



*  Contained  ether. 


Chemical  Properties. 

Loss  in  weight  on  heating:  The  oleoresins  prepared  in  the 
laboratory  lost,  as  a  rule,  between  11  and  13  per  cent,  of  their 
weight  on  heating  at  110° C,  whereas  the  loss  in  the  case  of  the 
commercial  samples  was  about  twice  as  great.  "While  this  dif- 
ference may  have  been  due  to  the  employment  of  different 
methods  in  the  making  of  these  preparations  (a  vacuum  pan 
having  probably  been  used  in  the  r-emoval  of  the  solvent  in  the 
case  of  the  commercial  products),  it  is  more  likely  the  re- 
sult of  the  presence  of  a  greater  amount  of  volatile  oil  in  the 
drugs  from  which  the  latter  were  prepared.     The  loss  in  weight 


174 


DU  MEZ— THE  GALENICAL  OLEORESINS 


as  found  for  the  preparations  examined  in  the  laboratory  is  given 
in  the  tables  which  follow. 

Table  70 — Laboratory  preparations — loss  in  weight  on  heating. 


Sample 
No. 

Date. 

Observer. 

Solvent. 

Per  ct.  of  loss 
on  heating. 

1 

1916 

DuMez 

At  110°  C 
12.82 

2 

Acetone 

11.92 

5 

•• 

7.34 

6  . 

•« 

Ether ...... ....V.....V.V... 

11.54 

3 

" 

11.08 

4  .      .   .. 

'» 

Petrol,  ether 

11.50 

Table  80.  — Commercial  samples — loss  in  weight   on  heating. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent  of 
loss  on 
heating 

1. 

1916 

DuMez   

Lilly  &  Co 

At  110°  C 
18.90 

2 

Squibb  &  Sons 

21.391 

3 



Sh  arp  &  Dohme 

22.97 

*  The  presence  of  ether  could  be  detected  by  the  odor. 

Ash  content:  The  ash  content  of  the  oleoresin  prepared  with 
acetone  was  found  to  be  0.28  per  cent.,  whereas,  that  of  the 
preparation  made  with  ether  was  only  0.14  per  cent.  The  values 
obtained  for  the  commercial  samples  examined  also  showed  this 
variation  due  to  the  nature  of  the  solvent.  Copper,  although 
•detected  in  two  of  these  preparations  (commercial  oleoresins), 
was  present  in  such  small  quantities  that  the  results  were  not 
affected  materially  thereby.  The  following  tables  show  the 
results  obtained  in  the  ash  determinations  made  in  the  laboratory. 


Table  81. — Ash  contents  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent  of 
ash 

1 

1916 

DuMez  

Alcohol 

Acetone 

0.42 

2 

0.30 

3 

0.26 

i 

•' 

Ether 

0.28 

5 

•« 

0  14 

6 

•• 

Petrol,  ether 

0.06 

OLEORESIN  OF  GINGER 


175 


Table  82.— Ash  contents  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent  of 
ash 

Foreign 
constituents 

1916 

DuMez  

Squibb  &  Sons 

0.15  » 

0.26 

0.27 

2 

3, 

Lilly  &  Co        

Copper 

Sharp  &  Dohme 

1  Contained  ether. 

Acid  nuynher:  The  acid  numbers  obtained  for  the  oleo- 
resins prepared  in  the  laboratory  were  found  to  be  fairly 
uniform  regardless  of  the  solvent  employed  in  extracting  the 
drug,  except  in  the  case  of  petroleum  ether,  when  the  value 
found  was  low,  namely,  11.2.  The  values  obtained  for  the  com- 
mercial samples  examined  were  almost  identical  with  those  ob- 
tained for  the  laboratory  preparations,  even  though  the  former 
in  all  cases  contained  about  twice  as  much  volatile  matter  (gen- 
erally essential  oil,  in  one  case,  unevaporated  solvent  in  addi- 
tion) as  the  latter.  The  values  obtained  for  this  constant  in  the 
laboratory  are  given  in  the  tables  which  follow. 

Table  83 — Acid  numbers  of  oleoresins  prepared  in  the  laboratory- 


Sample 

,.5?°.- 

Date 

Observer 

Solvent 

Acid 
number 

1 

1916 

DuMez 

Alcohol 

13  9 

2 

Acetone 

14  5 

3 

13  8 

4 

•  ' 

13  5 

5 

Ether 

13  7 

6 

" 

Petrol,  ether 

11  2 

Table  84 — Acid  numbers  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Acid 
number 

1 

1916 

DuMez 

Lilly  &Co 

13  3 

2::::::::: 

Squibb  &  Sons... 

13  8  > 

S 

»» 

Sharp  &  Dohme 

14  0 

1  Contained  ether. 


Saponification    value:    Saponification    values    of    103.4    to 
110.4   were   obtained   for  the   oleoresin   when   prepared   with 


176 


DU  MEZ— THE  GALENICAL  OLEORESINS 


acetone.  For  the  preparation  in  which  ether  was  employed  as 
a  menstruum  in  extracting  the  drug,  a  saponification  value  of 
102.9  was  obtained.  The  comparatively  low  values  obtained  for 
the  commercial  samples  examined  are  to  be  accounted  for  by 
the  fact  that  in  all  cases,  they  contained  nearly  twice  as  much 
volatile  matter  (presumably  essential  oil)  as  the  laboratory 
preparations.  The  values  found  for  this  constant  are  given  in 
the  tables  which  follow. 


Table  85 — Saponification  values  of  oleoresins  prepared  in  the  laboratory. 


Sample 
,      No. 

Date 

Observer 

Solvent 

Saponifica- 
tion value 

1 

1916 

DuMez 

Alcohol 

119  4 

2 

103.4 
110  4 

3 

«» 

4, 

" 

•    ••      • 

105.7 

« 

»» 

Ether 

102  9 

5 

•' 

Petrol,  ether 

78.1 

Table  86 — Saponification  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

1 

1916 

DuMez 

Sharp  &  Dohme 

94.1 

2..  .. 

SQuibi)&  Sons 

98.41 

3 

" 

Lillv&  Co 

89.9 

*  Contained  a  trace  of  ether. 


Iodine  value:  Iodine  values  of  122.4  to  124.1  were  ob- 
tained for  the  oleoresin  when  prepared  with  acetone.  The 
preparations  made  with  alcohol  or  ether  gave  values  very 
near  the  same,  whereas,  the  value  of  this  constant  was  some- 
what higher  (126.9)  when  petroleum  ether  was  the  solvent  em- 
ployed. With  respect  to  the  commercial  samples,  the  values 
found  were  lower  in  all  cases.  In  one  instance,  this  was  due 
to  the  presence  of  unevaporated  solvent,  while,  in  the  other  cases 
it  is  to  be  attributed  to  the  relatively  large  amount  of  volatile 
matter  (essential  oil)  present.  The  iodine  values  found  for  the 
preparations  examined  in  the  laboratory  follow. 


OLEORESIN  OF  GINGER 


177 


Table  87. — Iodine  values  of  oUoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Iodine  value 

1 

1916 

122.3 

2 

Acetone 

122  4 

3 

»' 

111.5  1 

4 

" 

" 

124.1 

5 

Ether 

121.1 

6 

"          

Petrol,  ether .. 

126.9 

Tlie  drug  in  this  instance  was  extracted  by  simple  percolation. 
TabLiE  88. — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Iodine  value 

1 

1916 

DuMez  

?quibb&9ons  

104. 2> 

2 

Lilly  &  Co 

109.9 

3 

" 

Sharp  &  Dohme  

112  0 

*  Contained  ether. 

Special  Qualitative  Tests. 

Most  of  the  qualitative  methods  which  have  been  mentioned  in 
connection  with  the  standardization  of  this  preparation  are  of 
the  nature  of  tests  for  the  detection  of  adulterations.  The  oleo- 
resin  of  capsicum^  is  the  adulterant  which  appears  to  have  re- 
ceived special  attention,  several  methods  for  detecting  its  pres- 
ence having  been  reported. 


Tests  for  the  Presence  of  the  Oleoresin  of  Capsicum 

La  Wall,  in  1910,  pointed  out  the  necessity  of  a  test  for  the 
presence  of  the  oleoresin  of  capsicum  as  he  had  observed  that 
many  of  the  commercial  samples  of  the  oleoresin  of  ginger  used 
in  the  preparation  of  ginger  ale  extracts  were  adulterated  with 
this  substance.  At  the  same  time,  he  also  described  a  method 
whereby  this  form  of  adulteration  might  be  detected.  His 
method  is  almost  identical  with  that  of  Garnett  and  Grier  pub- 
lished in  1907,  both  being  based  on  the     destruction    of    the 


1  While  the  oleoresin  of  capsicum  per  se  may  occassionally  be  added  to  the 
finished  product,  it  Is  thought  that  the  adulteration  is  usually  accomplished 
^y  mixing  capsicum  with  the  ginger  previous  to  the  extraction  of  the  oleoresin. 


178  I^U  MEZ— THE  GALENICAL  OLEORESINS 

pungent  principles  ( ginger ol)  of  the  oleoresin  of  ginger  with 
alkalies,  whereby  the  pungent  principle  (capsiciri)  of  the  oleo- 
resin of  capsicum  remains  unaltered.  As  it  was  subsequently 
found  that  the  pungent  principles  of  the  former  were  not  com- 
pletely destroyed  by  this  treatment,  Nelson  proposed  a  modi- 
fication of  the  above  methods,  in  which  he  makes  use  of 
manganese  dioxide  for  completing  the  disintegration  of  these 
constituents.     Full  descriptions  of  these  methods  follow : 

Method  of  Garnett  and  Grier  (1907) :  Digest  1  gram  of  the  oleoresin 
for  15  minutes  on  a  water  bath  with  a  small  quantity  of  caustic  alkali 
dissolved  in  alcohol.  Evaporate  the  solution  to  remove  the  alcohol  and 
make  the  residue  faintly  acid  with  hydrochloric  acid.  Transfer  the  liquid 
to  a  test  tube  and  shake  it  with  5  cubic  centimeters  of  ether  which  have 
previously  been  used  to  rinse  the  dish.  Allow  the  mixture  to  stand  quietly 
and  then  taste  the  separated  ethereal  layer.  If  sharply  pungent,  adultera- 
tion with  capsicum  is  indicated. 

Method  of  La  Wall  (1910) :  Add  10  cubic  centimeters  of  half -normal 
alcoholic  potassium  hydroxide  solution  to  1  gram  of  the  oleoresin  contained 
in  a  shallow  porcelain  dish  and  evaporate  to  dryness  on  a  water  bath.  Dis- 
solve the  residue  in  50  cubic  centimeters  of  water  and  transfer  the  solution 
to  a  separatory  funnel.  Add  20  cubic  centimeters  of  ether  and  shake  vigor- 
ously. After  allowing  the  mixture  to  stand  until  the  ether  has  separated, 
run  the  latter  off  on  a  watch  glass  and  expose  it  until  the  solvent  has  all 
evaporated.  The  residue  should  have  a  warm  camphoraceous  taste.  A 
sharp  pungent   taste  indicates  adulteration  with   capsicum. 

Method  of  Nelson  (1902) :'  Add  10  cubic  centimeters  of  double-normal 
alcoholic  potassium  hydroxide  solution  to  one  gram  of  the  oleoresin  contained 
in  a  porcelain  dish  and  evaporate  on  a  steam  bath.  Add  about  0.1  gram 
of  powdered  manganese  dioxide  and  5  to  10  cubic  centimeters  of  water, 
and  continue  heating  for  about  20  minutes,  or  until  all  of  the  volatile  oil 
has  been  expelled.  Cool,  acidify  with  dilute  sulphuric  acid  and  extract 
at  once  with  petroleum  ether.  Evaporate  the  petroleum  ether  solution  in  a 
small  crucible,  keeping  the  residue  within  as  small  an  area  as  possible.  When 
all  of  the  solvent  has  evaporated,  apply  the  tongue  to  the  residue,  being 
careful  to  keep  the  material  on  the  tip.  If  capsicum  is  present,  the  char- 
acteristic burning  sensation  will  soon  be  felt. 

The  latter  is  the  method  which  was  employed  in  making  the 
test  in  the  laboratory.  In  no  case,  however,  was  capsicum  de- 
tected in  the  samples  examined. 


« Journ.  Indust.  and  Eng.  Chem.  (1910),  2,  p.  419. 


OLEORESIN  OF  GINGER 


119 


Special  Quantitative  Tests. 

While  tlie  matter  of  determining  the  quality  of  the  unadulter- 
ated product  has  apparently  received  but  little  attention,  two 
distinct  methods  have,  nevertheless,  been  made  use  of  in  its 
evaluation.  They  are  the  methods  of  Garnett  and  Grier  for  the 
determination  of  the  gingerol  content,  and  the  physiological  test 
employed  by  the  H.  K.  Mulford  Company. 

Methods  for  the  Estimation  of  the  Gingerol  Content. 

The  only  method  of  an  analytical  nature  which  has  been  sug- 
gested for  the  quantitative  evaluation  of  this  oleoresin  is  based 
on  the  fact  that  the  pungent  principles,  gingerol,  are  more 
readily  soluble  in  60  per  cent  alcohol,  than  in  petroleum  ether, 
A  description  of  the  manner  in  which  this  assay  is  carried  out 
follows. 

Method  of  Garnett  and  Grier  (1909):  Dissolve  the  gingerol  by  boiling 
about  1  gram  of  the  oleoresin  with  several  portions  of  petroleum  ether^ 
filter  the  solutions  thus  obtained  and  remove  the  solvent  bj  evaporation 
on  a  water  bath.  Dissolve  the  residue  in  alcohol  (60  per  cent.)  added  in 
three  separate  portions,  shake  the  united  alcoholic  solutions  with  a  small 
amount  of  petroleum  ether  to  remove  traces  of  fat  and  remove  the  alcohol 
from  the  hydro-alcoholic  portion  by  evaporation.  Shake  the  residual  liquid 
with  3  portions  of  ether  added  successively,  filter  the  combined  shakinga 
into  a  tared  flask,  remove  the  ether  by  evaporation  on  a  water  bath,  dry 
at  100°C  and  weigh.  In  the  final  shaking  out,  carbon  disulphide  or  chloro- 
form may  be  used  in  place  of  the  ether. 


The  use  of  this  method  in  the  laboratory  has  shown  that  it 
gives  fairly  constant  results,  and,  as  it  is  easily  carried  out,  it 
should  prove  to  be  of  practical  value.  The  results  obtained  in 
the  examination  of  oleoresin s  prepared  in  the  laboratory  and 
those  obtained  from  commercial  sources  are  given  in  the  fol- 
lowing tables : 

Table  89 —  Gingerol  content  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Gingerol 
content 

1 

1916 

DuMez 

Alcohol 

Percent. 
27  2 

2 

Acetx)ne 

23.2 

3 

" 

Ether 

27.5 

4 

" 

Petrol  ether    . 

43  9 

ISO 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  90 — Oingerol  content  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Gingerol 
content 

1 

1916 

DuMez 

Li  lly  «Sz;  Co              

Per  cent. 
19.5 

12 

Sharp  &  Dobme 

24.0 

Z 

" 

flQuibt)  &  Sons    

28.2 

The  first  of  the  preceding  tables  shows  that  the  gingerol  con- 
tent varies  with  the  solvent  employed  in  the  preparation  of  the 
oleoresin.  Further,  that  this  variation  is  not  in  inverse  ratio 
to  the  yield  of  oleoresin  obtained  as  might  be  expected,  but  is 
•exceptionally  low  in  the  case  of  acetone  due  to  the  fact  that  it  is 
a  difficult  matter  to  completely  exhaust  the  drug  when  the  lat- 
ter is  the  solvent  used. 

The  low  gingerol  content  of  two  of  the  commercial  samples  as 
shown  in  the  second  table,  points  to  the  use  of  acetone  in  their 
preparation.  A  similar  effect  might,  however,  be  produced  when 
ether  or  alcohol  are  employed  if  the  ginger  used  is  of  poor 
quality  (low  in  gingerol  content,)  or  if  percolation  is  termin- 
ated before  complete  exhaustion  of  the  drug  has  taken  place. 
The  oleoresin  obtained  from  Squibb  and  Sons  is  stated  to  have 
been  prepared  with  ether,  which  statement  is  confirmed  by  the 
result  obtained  in  the  determination  of  the  gingerol  content  as 
is  also  shown  in  the  second  table. 


Physiological  Tests. 

The  H.  K.  Mulford  Company  reports  the  use  of  a  physiologi- 
-cal  test  for  determining  the  quality  of  this  oleoresin.  As  an 
arbitrary  standard,  the  firm  has  taken  a  preparation  which  is 
pungent  to  the  taste  in  a  maximum  dilution  of  1  to  20,000'. 
While  there  is  no  information,  at  hand  to  indicate  what  solvent 
was  employed  as  the  diluent,  experience  in  the  laboratory  has 
shown  that  dilute  alcohol  (50  per  cent.)  may  be  used  for  this 
purpose.  After  vigorously  shaking  the  oleoresin  with  alco- 
"hol,  the  resulting  solution  should  preferably  be  filtered  before 
applying  to  the  tongue.  AlUiough  no  extensive  series  of  ex- 
periments were  made  with  this  test  in  the  laboratory,  the  results 
obtained  would  appear  to  indicate  that  the  above  standard  is 
rather  low  as  the  pungency  in  the  preparations  examined  was 


OLEORESIN  OF  LUPIILIN  lg% 

easily  perceptible  in  dilutions  of  1  to  30,000.  In  view  of  the 
fact  that  personal  idiosyncrasy  must  be  a  factor  in  applying  this- 
test,  the  use  of  the  previously  described  method  for  the  estima- 
tion of  the  gingerol  content  is  thought  to  be  more  preferable  for 
use  in  this  connection. 

Adulterations 

There  is  no  evidence  to  show  that  the  oleoresin  as  prepared 
for  pharmaceutical  use  is  adulterated.  La  Wall,^  however,  states 
that  the  commercial  article  used  in  the  manufacture  of 
ginger  ale  frequently  contains  oleoresin  of  capsicum. 

A  trace  of  copper  was  found  in  most  of  the  commercial 
samples  examined.      See  under  **Ash  content." 

Oleoresin  of  Lupulin 
Synonyms 

Aetherisches  Lwpulinextrdkt,  Nat.  Disp.  1879. 

Extractum  Lupulini,  Hirsh,  Univ.  P.  1902,  No.  1222. 

Extractum  Lupulini  aethereum,  Nat.  Disp.  1879. 

Oleoresina  Lupulinae,  U.  S.  P.  1860. 

Oleoresina   Lupulini,  U.  S.  P.   1880. 

Oleoresine  de  Lupuline,  U.  S.  Disp.  1907. 

Ethereal  Extract  of  Lupulin,  King's  Am.  Disp.   (1900),  p.  1333. 

History 

The  first  mention  of  the  oleoresin  of  lupulin  which  could  be 
f  ound  in  pharmaceutical  literature  appeared  in  Procter 's  article, 
'^  Formulae  for  fluid  extracts  in  reference  to  their  more  general 
adoption  in  the  next  Pharmacopoeia,"  published  in  1859.. 
Procter's  oleoresin  was  in  reality  an  ethereal  extract,  ether  hav- 
ing been  the  menstruum  employed  in  exhausting  the  drug.  In 
this  connection,  it  is  interesting  to  note  that  the  extract  prepared 
with  the  use  of  alcohol  had  previously  been  brought  to  the 
notice  of  the  American  pharmacist  by  Livermore  in  1853,  while 
the  attention  of  the  European  pharmacist  had  been  directed  ta 
the  same  by  Planche  as  early  as  1823.  The  oleoresin  was  first 
admitted  to  the  United  States  Pharmacopoeia  in  1860,  in  which 
it  remained  official  for  more  than  half  a  century,  having  been 


1  La  Wall    (1910). 


282  ^U  MEZ— THE  GALENICAL.  OLEORESINS 

omitted  from   the  present   revised  edition.     It  has  never  re- 
<jeived  recognition  by  any  of  the  foreign  pharmacopoeias. 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

Lupulin  has  not  been  included  in  the  late  edition  of  the  United 
States  Plfiarmacopoeia,  In  the  preceding  edition,  it  was  defined 
as  ^'the  glandular  trichomes  separated  from  the  fruit  of  Humvr 
lus  LupiUus  Linne  (Fam.  Moraceae).^' 

The  drug,  as  it  occurs  on  the  market,  is  of  varying  degrees  of 
purity  due,  principally,  to  the  method  of  obtaining  it  While 
some  of  it  is  probably  obtained  by  picking  the  scales  from 
the  fruits  and  then  shaking  or  rubbing  the  glands  through  a 
fine  sieve,  the  bulk  of  the  commercial  article  consists  of  the 
-sweepings  gathered  up  from  the  floors  of  the  hop  bins.^  Such 
being  the  case,  it  is  only  natural  to  expect  contamination  with 
sand  and  other  earthy  materials.  The  impurities,  in  part,  are 
usually  removed  by  washing  with  water  when  the  sand  settles 
to  the  bottom  and  the  lupulin  is  skimmed  off  and  dried. 

The  glands,  on  storing,  especially  if  exposed  to  the  air, 
undergo  a  change,  becoming  dark  brown  in  color  and  developing 
&  rancid  odor.  Rabak-  and  Russell,^  respectively,  have  shown 
one  of  the  changes  to  be  a  conversion  of  the  so-called  soft  resin 
into  the  hard.  The  development  of  the  disagreeable  odor  has 
been  attributed  to  the  formation  of  valeric  acid*  resulting  from 
the  oxidation  of  one  or  more  of  the  constituents.  In  view  of  the 
foregoing,  the  British  Pliarmacopma  directs  that  the  drug  be 
renewed  annually  and  rejected  as  soon  as  it  becomes  dark  in 
■color  or  developes  a  cheesy  odor. 

In  this  connection,  it  should  also  be  stated  that  hops  are  often 
sulphured  previous  to  storing.  To  what  extent,  if  any,  this 
treatment  affects  the  quality  of  the  lupulin  obtained  therefrom 
«-nd  later  the  oleoresin,  does  not  appear  to  have  been  determined. 


^  Flueckiger,  Pharmakognoise  des  Pflanzenreichs    (1891),  p.   255. 
«Bull.  No.  271.  U.  S.  Dept.  of  Agric.    (1913),  p.  13. 
'Bull.  No.  282.  U.   S.  Dept  of  Agric.    (1915),  p.   9. 
-•Bungener.  Pharm.  Journ.    (1884),  43,  p.  1008. 


OLBORESIN  OF  LUPULIN 


183 


Z7.  S.  P.  Text  and  Comments  Thereon. 

The  oleoresin,  which  was  official  in  the  United  States  PJiar- 
macopma  from  1860  to  1900,  has  been  omitted  from  the  last 
edition  (edition  of  1910). 

1864 

Oleoresina  Lupulinae 
Oleoresin  of  Lupulin 
Take  of  Lupulin*  twelve  troyounces;    distillation  on  a  water-bath,  eighteen 
Ether*  a  sufficient  quantity.  fluidounces  of  ether,'  and  expose  the 

Put  the  lupulin  into  a  narrow  eylin-    residue,  in  a  capsule,  until  the  remain- 
drieal  percolator,  press  it  firmly,  and    ing   ether     has     evaporated."     Lastly, 
gradually  pour  ether    upon    it    until    keep  the  oleoresin  in  a  wide-moutiied 
thirty    fluidounces    of    filtered    liquid    bottle,  well  stopped.^ 
have  passed.*     Eecover  from  this,  by 


1870 

Oleoresina  Lupulinae 
Oleoresin  of  Lapulin 


Take  of  Lupulin  *  twelve  troyounces ; 
Ether'   a   sufficient   quantity. 

Put  the  lupulin  into  a  narrow  cylin- 
drical percolator,  provided  with  a 
fltop-cock,  and  arranged  with  cover 
and  receptacle  suitable  for  volatile 
liquids,^  press  it  firmly,  and  gradually 
pour  ether  upon  it,  until  twenty  fluid- 


ounces  of  liquid  have  slowly  passed.* 
Eecover  the  greater  part  of  the  ether 
by  distillation  on  a  water-bath,"^  and 
expose  the  residue  in  a  capsule,  until 
the  remaining  ether  has  evaporated.' 
Lastly,  keep  the  oleoresin  in  a  wide- 
mouthed  bottle,  well  stopped.' 


1880 

Oleoresina  Lupulini 

Oleoresin  of  Lupulin 

[Oleoresina  Lupulinae,  Pharm.,  1870] 

Lupulin,*  one  hundred  'parts  ....100.  parts  of  liquid  have 
Stronger  Ether*,  a  sufficient  quantity. 
Put  the  lupulin  into  a  narrow  cylin- 
drical percolator,  provided  with  a 
«over  and  receptacle  suitable  for 
volatile  liquids,'  press  it  firmly,  and 
gradually  pour  stronger  ether  upon  ped,  wide-mouthed  bottle.' 
it,  until  one  hundred  and  fifty   (150) 


slowly  passed.* 
Recover  the  greater  part  of  the  ether 
by  distillation  on  a  water-bath,'  and 
expose  the  residue,  in  a  capsule,  until 
the  remaining  ether  has  evaporated.* 
Keep   the   oleoresin    in   a  well-stop- 


23^         DU  MEZ— THE  GALENICAL  OLEORESINS 


1890 

Oleoresina  Lupulini 

Oleoresin  of  Lupulin 

Lupulin/  one  hundred  grammes the  drug  is  exhausted.*    Recover  the 

100  Gm.  greater   part   of   the  ether  from  the 

Ether,^  a  sufficient  quantity.  percolate  by  distillation  on  a  water- 
Put  the  lupulin  into  a  cylindrical  bath/  and,  having  transferred  the 
glass  percolator,  provided  with  a  residue  to  a  capsule,  allow  the  re- 
stop-cock,  and  arranged  with  a  cover  maining  ether  to  evaporate  spontan- 
and  receptacle  suitable     for     volatile  eously.* 

liquids.^     Press  the  drug  very  lightly,        Keep    the   product    in    a   well-stop- 

and     percolate      slowly      with    ether,  pered  bottle,' 
added    in    successive    portions,     until 

1900 

Oleoresina  Lupulini 

Oleoresin  of  Lupulin 

JjupuVm,^  five  hundred  grammes Recover  the  greater  part  of  the  ace- 

500  Gm.  tone    from   the   percolate   by    distilla- 

Acetone,'  a  sufficient  quantity.  tion  on  a  water-bath,"*     and,     having 

Introduce  the  lupulin  into  a  cylin-  transferred  the  residue  to  a  dish,  al- 

drical  glass  percolator,  provided  with  low    the   remaining    acetone   to   evap- 

a  stop-cock,     and     arranged     with     a  orate  spontaneously  in  a  warm  place.* 

cover    and    a    receptacle    suitable    for  Keep  the  oleoresin  in  a  well-stoppered 

volatile  liquids.^       Press   the   powder  bottle.' 

very  lightly,     and     percolate     slowly  Average     dose. — 0.200  =  Gm.      200 

with  acetone,  added  in  successive  por-  milligrammes    (3  grains), 
tions,  until  the  lupulin  is  exhausted.* 


1)  For  description  of  the  drug,  see  page  1088  under  ''Drug 
used,  its  collection,  preservation,  etc." 

2)  The  solvents  which  have  been  used  for  the  purpose  of  ex- 
tracting lupulin  are  ether,  acetone  and  alcohol.  Of  these,  the 
first  two  have  been  recognized  at  different  times  by  the 
Pharmacopoeia,  acetone  being  the  solvent  which  was  directed 
to  be  used  by  the  edition  of  1900,  whereas  ether  was  specified 
in  previous  editions. 

With  respect  to  the  relative  values  of  the  above,  from  a 
therapeutical  standpoint,  a  statement  cannot  be  made  owing 
to  the  lack  of  specific  information  on  the  subject.  From  a 
pharmaceutical  standpoint,  however,   ether  and  acetone,  re- 


OLEORESIN  OF  LUPULIN  ^85 

spectively  possess  an  advantage  over  alcohol  in  that  they  ex- 
tract less  inert  material  and  yield  products  which  are  softer 
in  consistence  and  conform  more  closely  in  their  general 
properties  to  the  other  members  of  this  class  of  preparations. 
The  products  obtained,  even  when  using  acetone  or  ether,  are, 
however,  more  of  the  nature  of  an  extract  than  an  oleoresin. 
A  better  solvent  for  use  in  this  connection  would  appear  to 
be  petroleum  ether.  While,  it  has  apparently  never  received 
consideration  for  this  purpose,  it  appears  to  be  particularly 
well  adapted  to  the  same  in  that  it  completely  extracts  the 
valuable  constituents  of  the  drug  (see  soft  resins,  page  1095) 
with  but  little  of  the  inert  material  and  yields  a  product  of 
such  consistence  that  it  can  be  poured. 

3)  For  a  description  of  the  various  forms  of  percolation  con- 
forming to  the  pharmacopoeial  specifications  for  use  in  this 
connection,  see  Part  I  under  ''Apparatus  used." 

4)  The  various  editions  of  the  Pharmacopoeia  in  which  this 
preparation  has  been  official  have  directed  that  the  material 
composing  the  oleoresin  be  extracted  from  the  drug  by  simple 
percolation.  In  the  earlier  editions,  percolation  was  directed 
to  be  continued  until  a  certain  definite  amount  of  percolate 
was  obtained,  whereas,  the  pharmacopoeias  of  1890  and  1900 
required  that  the  operation  be  continued  until'  the  drug  was 
exhausted.  In  either  case,  the  quantity  of  solvent  required  is 
considerably  greater  than  that  which  is  necessary  to  com- 
pletely exhaust  the  drug  when  some  form  of  continuous  ex- 
tractor is  used.  Since  the  quality  of  the  finished  product  is 
the  same  in  both  cases,  it  is  thought  that  the  later  method  of 
extraction  is  to  be  preferred. 

5-6)  Owing  to  the  fact  that  certain  constituents  of  the  oleo- 
resin are  prone  to  undergo  changes  when  the  latter  is  exposed 
to' the  air  (see  page  1088  under  ''Drug  used,  its  collection,  pres- 
ervation, etc.''),  the  pharmacopoeial  directions,  that  the  last 
portions  be  allowed  to  evaporate  spontaneously,  are  unfortu- 
nate. It  is  thought  that  a  better  procedure  would  be  to  evap- 
orate the  solvent  completely  at  the  temperature  of  the  water 
bath,  thereby  considerably  shortening  the  time  of  exposure. 

8)  For  the  reasons  just  mentioned,  the  finished  product 
should  be  kept  in  well-stoppered  bottles. 


186 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Yield 


The  yield  of  oleoresin  to  ether  is  usually  given  in  the  text- 
books and  treatises  on  pharmacy  as  50  to  60  per  cent.,  while  a 
yield  of  32.49  to  70.8  per  cent,  has  been  reported  in  the  journals. 
The  irregularity  in  the  quality  of  the  lupulin  as  ordinarily  found 
on  the  market  very  likely  accounts  for  this  variation.  The 
drug,  when  of  good  quality  should  give  a  yield  of  at  least  60 
per  cent.  The  following  tables  show  the  variation  in  the  yield 
as  reported  in  the  literature,  also,  the  results  obtained  in  the 
laboratory. 

Table  91 — Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
solvents 

Remarks 

1853 

Livermore 

Trimble 

Per  ct. 
66.00 

Per  ct. 

Per  ct. 

Per  ct. 

1888 

60.59 

70.  fO 
86.50 
52.00 
65.00 

56.00 
54.00 
60.10 
66.70 
34.00  to 
65.80 

47.00 
50  00 
5:^.00 
57.70 
58.90 
62.10 
60.0+ 

44.94  to 
65.60 

63.96  to 
77.82 

Below 
60.00 

32.49 
55.18 
57.06 
44.20 
54.70 
55.00 
55.30 
.55.50 
57.10 
58.60 
68.20 
69.20 

J     Benzin 
(           7.04 

1892 

71.00 

1892 

Sherrard 

1907 

Van  der  Harst .. 

Dohme  and  En- 

1908 

1909 

Parson  .  , 

Bernegau 

1909 

Results   obtained   In    the    ex- 

1909 

Dohme    &     En- 
gelhardt 

traction  of  10  samples  ofilu- 
pulin. 

Berneg'au 

1911 

■ 

Francis 



1911 

Seven   of    8    samples    yielded 

1913 

Gane 

Patf'h 



more  than  60  per  cent,  of  ex- 
tractive to  ether.            •       rS 
Results  ol)tained    in    the    ex- 

1913 

traction  of  .4  samples  of  lu- 
pulin. 
Results  obtained    in   the    ex- 

1913 

Engrelhardt 

traction  of  53  samples  of  lu- 
pulin. 
Eiffht  of  12  samples  of  lupulin 

1914 

Rippetoe 

extracted  srave  below  60  per 
cent,  of  ether  soluble  matter. 

1915 

: 



. :!_:=» 

OLEORESIN  OF  LUPULIN 


18T 


Table  92 — Yield  of  oleoresin  as  obtained  in  the  laboratory. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Benzin 

Remarks 

1910 

DuMez&  Netzel. 

Per  ct. 
78.13 

Per  ct. 
68.42 

Per  ct. 
66.71 

Per  cent 
14.46 

Represents  the   yiel* 
obtained     using'     a 
Soxhlet's  extraction- 
app ,    except  in  the 
case  of  alcohol. 

Chemistry  of  the  Drug  and  Oleoresin 

Tabulation  of  Constituents 

The  chemistry  of  lupulin^  per  se  has  received  comparatively 
little  attention,  although,  a  very  considerable  knowledge  con- 
cerning its  constituents  has  been  gained  through  the  work  of 
the  brewing  chemists  and  others^  on  hops.      The  isolation  of  the 


II 


1  The  following  have  reported  more  or  less  complete  analyses  of  lupulin : 
Ives,  Silliman's  Am.  Journ.  of  Science  (1820),  2.  p.  303;  Payen,  Pelletan  and' 
Chevalier,  Journ.  de  Pharm.  et  de  Chim.  (1822),  8,  p.  209;  Personne,  Ihid. 
(1854),  59,  p.  329;  Chapman,  The  Hop  and  its  Constituents.  The  Brew- 
ing Review,  London,   (1905). 

'  Power,  Tutin  and  Rogerson,  who  have  completed  one  of  the  most  recent 
as   well   as  extensive  pieces  of  work   on  the   constituents   of   the   hop,   have- 
isolated  the  following  substances : 
I     Volatile  oil 

Alcoholic  Extract  soluble  in  water: 
1.     Choline   (C.H^^O^N.) 

1-Asparagine   (C^HgOjNj.) 
Potassium   nitrate 
Tannin 

Sugar  forming  a  d-phenylhydrazone,  m,  p.   208. 
Amorphous  bitter  material. 
Volatile  base  having  a  coniine-like  odor. 
Alcoholic  extract  insoluble  in  water: 

1.  Hentriacontane    (Cg^Hg^.) 

2.  Ceryl  alcohol   (C^-H^gO.) 

3.  Phytosterol    (C^.H.gO.) 

4.  A   phytosterolin,   phytosterol   glucoside    (Cg^HjgOg.) 

5.  Volatile  fatty  acids:  formic,  acetic,  butyric,  valeric,  /3-isopro^ 
pylacrylic   (CgH,„OJ,  and  nonoic. 

6.  Saturated  and  unsaturated  non-volatile  acids:  palmitic,  ste- 
aric, cerotic,  an  isomeride  of  arachidic  (C2oH^02),  cluytinlc 
and  linolic. 

A      new     bitter      crystalline      phenolic      substance,      humulol 

(C,,H,,0,) 
A  new  tasteless  crystalline  phenolic  substance,  xanthonumoF 

(Cj3H,,0„.) 
Journ.  Chem.   Soc.    (1913),  103,  p.  1267. 


Ill 


7. 


8. 


288  ^U  MEZ— THE  GALENICAL  OLEORESINS 

following  constituents  of  pharmaceutical  interests  has  been  re- 
ported: Volatile  oil,  resin,  wax,  alkaloids  and  inorganic  sub- 
stances. Chapman^  gives  the  composition  of  the  ethereal  ex- 
tract as  follows: 

o-resin 18.06  per  cent. 

jS-resin     67.74  "       " 

Wax     0.28  "       " 

Other  constituents  (fat,  oil,  7-resin,  etc.) 13.64  "       " 

Ash    0.27  "       " 

Occurrence  and  Description  of  Individual  Constituents. 

Volatile  Oil^  The  volatile  oil  obtained  by  distillation  with 
steam  is  a  pale  yellow,  or  colorless,  mobile  liquid  possessing  a 
fragrant  and  characteristic  odor,  and  a  slightly  burning  taste. 
It  is  almost  insoluble  in  water,  to  which,  however,  it  imparts  its 
odor,  and  only  slightly  soluble  in  dilute  alcohol.  It  is  soluble 
in  ether,  petroleum  ether,  chloroform  and  the  other  volatile  oil 
solvents.  The  specific  gravity  at  20° C  is  0.8357  to  0.8776,  and 
the  specific  rotatory  power,  [alo^*^,  is  0.20  to  0.58.^ 

According  to  Chapman,^  the  oil  is  composed  of  the  terpene, 
myrcene,  (CioHjg),  40  to  50  per  cent;  inactive  linalool,  a  fraction 
of  1  per  cent ;  linalyl  isononoate,  a  fraction  of  1  per  cent ;  the 
sesquiterpene,  humulene^  (C15H24),  about  40  per  cent;  and 
probably  some  ether  of  geraniol  with  a  small  amount  of  a  diter- 
pene.  Rabak,^  who  has  more  recently  completed  an .  investiga- 
tion of  the  constituents  of  the  oil,  states  that,  in  addition  to 
myrcene  and  humulene,  the  oil  contains  the  heptoic,  octoic  and 
nonoic  acid  esters  of  myrcenol  with  traces  of  free  fatty  acids  and 
probably  some  free  alcohols. 

As  much  as  2  per  cent  of  volatile  oil  has  been  obtained  from 
lupulin  by  steam  distillation.^ 

Resin.  The  chemical  constitution  of  the  so-called  "hop 
resins ' '  is  still  an  unsolved  problem,  the  literature  being  replete 


^  Ihid,  p.  81.  The  hop  and  its  constituents.  The  Brewing  Review,  Lon- 
don  (1905). 

*The  following  references  are  to  the  earlier  literature  on  the  volatile  oil: 
Payen,  Felletan  and  Chevalier  and  Personne,  1.  c.  ;  Wag'ner,  Journ.  f.  prakt. 
Chem.    (1853),  58,  p.  351;  Ossipon,  Ibid.    (1886),  142,  p.  238. 

"  Chapman,  I.  c. 

« Ibid. 

'  E.  Deussen.  who  has  determined  the  constitution  of  humulene,  finds  it  to 
%e  1-caryophyllene.     Journ.   f.   prakt.  Chem.   (1911),    83,   p.   483. 

8  Journ.  Agric.  Research    (1914),  2,  p.  115. 

•Payen,  Pelletan  and  Chevalier,  I.  c.     See  also  Semmler,  Z.  c. 


OLEORESIN  OF  L.UFULIN  189 

with  vague  and  contradictory  statements.^"  Foi  practical  pur- 
poses, the  classification  of  Hayduck^^  appears  to  be  the  most 
useful.  This  investigator  distinguishes  three  resins,  which  he 
designates  a,  (3  and  y,  according  to  their  solubility  in  petroleum 
ether  and  their  behavior  toward  a  solution  of  lead  acetate.  The 
a-  and  /3-  resins  are  soluble  in  petroleum  ether,  and  are  further 
known  as  the  "soft  resins,"  being  of  a  soft  consistence  at  the 
ordinary  temperature.  The  y-resin  is  insoluble  in  petroleum 
ether,  but  soluble  in  ether  or  alcohol.  It  is  also  known  as  the 
''hard  resin." 

The  soft  resins  are  supposed  to  contain  the  valuable  bitter 
substances  present  in  hops.  From  these  resins,  Lintner  and 
SchnelP"  isolated  two  crystalline  bitter  substances  of  an  acid 
nature.  One  of  these,  C15H24O4,  they  proposed  naming 
**humulon;"^^  the  other,  they  have  designated  ''lupulic  acid."^* 

According  to  Chapman,  the  total  resins  constitute  more  than 
55  per  cent,  of  the  lupulin.^^ 

Wax.  According  to  Lermer^^  the  wax  is  insoluble  in  90  per 
cent  alcohol  and  can  be  obtained  by  treating  the  ethereal  extract 
with  this  solvent.  He  identified  it  as  myricyl  palmitate.  As 
Power,  Tutin  and  Rogerson^''  report  the  presence  of  ceryl  alco- 
hol and  cerotic  acid  in  hops,  it  is  quite  probable  that  ceryl 
cerotate  is  also  a  constituent  of  the  wax. 

Alkaloids.  Choline^*  (C5H15O0N)  is  the  only  base  occurring 
in  lupulin,  the  identity  of  which  has  been  established.  There 
is,  however,  considerable  evidence  of  the  presence  of  a  volatile 


^oThe  theory  advanced  by  Seyffert  (Zeitschr.  ges.  Brauw.  (1896),  19,  p.  1 
namely,  that  the  hop  resins  are  mixtures  of  substances  in  a  progressive  stajt© 
of  change  is  probably  correct.  Confirmation  of  this  theory  is  to  be  found 
in  the  work  of  Russell  who  states  that  a  portion  of  the  "soft  resin'"  is  con- 
verted into  the  "hard  resin"  upon  keeping  the  hops  in  storage.  U.  S.  Dept. 
Agric,  Bull.  No.  282  (1915),  p.  9. 

11  Wochenschr.  f.  Brau.   (1887),  4,  p.  397;  Ihid.    (1888),  5,  p.  937. 

"Zeitschr.  ges.  Brauw.  (1904),  27,  p.  666. 

"  "Humulon"  is  very  likely  identical  with  the  "hop-bitter  acid"  of  H.  feun- 
gener,  (Bull.  Soc.  Chim.  (1886),  45,  p.  487),  and  the  "a-lupullc  acid"  of 
Barth.  Zeitschr.  ges.  Brauw.  (1900),  23,  pp.  509,  587.  664,  672  and  694. 

"  "Lupulic  acid"  corresponds  to  the  ")8-lupulic  acid"  of  Barth,  I.  c. 

^l.  c. 

«Dingler's  Folytech.  Journ.   (1863),  169,  p.  54. 

"Z.  c. 

"  Grless  and  Harrow  have  shown  that  hops  contain  not  over  0.02  per  cent, 
of  choline.     Ber.  der  deutsch.  chem.  Ges.    (1885),  18,  p.  717. 


|[90  ^U  MEZ— THE  GALENICAL  OLEORESINS 

alkaloid  possessing  a  coniine-like  odor.  Griessmayer/®  who 
first  noted  its  presence,  gave  it  the  name  ''lupuline." 

In  1885,  Williamson^*^  reported  the  isolation  of  a  crystalline 
alkaloid  from  wild  American  hops.  He  gave  it  the  name 
*'hopeine,"  and  assigned  to  it  the  formula,  C18H20NO4.  HoO. 
Ladenburg,^^  who  examined  a  sample  of  the  material  thought 
it  to  be  a  mixture  of  morphine  and  a  more  soluble  base.^^  As 
further  work^^  along  this  line  has  failed  to  confirm  the  findings 
of  Williamson,  the  presence  of  a  crystalline  alkaloid  must  be 
considered  doubtful. 

AsJi,  Analyses  of  the  ash  of  lupulin  have  apparently  not 
^been  reported  to  date.  However,  Wehmer^  states  that  Ca,  CI 
and  SiOa  are  present  in  the  ash  from  all  parts  of  the  hop  plant, 
and,  as  Na,  Mg,  Fe,  Al,  and  H3PO4  were  identified  in  the  ash 
of  the  oleoresins  examined  in  the  laboratory,  it  is  quite  probable 
that  the  constituents  of  lupulin  ash  are  identical  with  those 
present  in  the  ash  of  hops.^ 

There  is  a  great  variation  in  the  quantity  of  ash  obtained 
from  commercial  samples  of  lupulin  owing  to  contamination 
with  sand  and  other  earthy  matter.  Barth^  gives  the  yield  of 
ash  as  9.5  to  24.4  per  cent,  while  Flueckiger*  states  that  a  good 
sample  of  lupulin  should  give  about  7.0  per  cent.  Accord- 
ing to  Keller,^  lupulin,  washed  free  from  all  earthy  matter, 
yielded  only  2.37  per  cent,  of  ash. 

Constituents  of  Therapeutic  Importance, 

There  appears  to  be  considerable  doubt  at  the  present  time 
as  to  the  value  of  the  oleoresin  of  lupulin  as  a  therapeutic 
agent.      The  presence  of  the  soluble  bitter  principles  is  said  to 


"Dingrler's  Polytech.  Journ.  (1874),  212,  p.  67.  See  also  Power,  Tutin  and 
Rogerson,  Z.  c. 

»Pharm.  Ztg.   (1885),  30  p.  620. 

»Ber.  der  deutsch.  Chem.  Ges.    (1886),  19,  p.   783. 

*■  Williamson,  in  a  second  publication,  agrees  with  the  findings  of  Laden- 
burg  and  assigns  the  name  hopeine  to  the  more  soluble  base.  Chem.  Zeit 
(1886),  10,  p.  491. 

*•  GreshofE  could  not  obtain  a  crystalline  alkaloid  from  lupulin.  Dingler's 
Polytech.  Journ.   (1887),  266,  p.  316. 

iWehmer,  Die  Pflanzenstoffe.  Jena  (1911).  p.  100. 

•Richardson,  in  an  examination  of  hop  ash,  identified  the  elements,  Na,  K. 
Ca,  Mg.  Al  and  Fe,  and  the  acids,  HgPO^,  HjCOj  and  H^SiO,.  Wochenschr. 
Brau.  (1898),  15,  p.  160. 

•Zeitschr.  ges.  Brauw.   (1900),  23.  p.  509. 

•Flueckiger,  Pharmakofjnosie  des  Pflanzenreiches.  Berlin   (1891),  p.  257. 

•Fharm.  Ztg.    (1889),  34,  p.   533. 


OLEORESIN  OF  LUPULIN  191 

impart  to  it  the  properties  of  a  simple  bitter.^  The  somewhat 
-general  belief  that  the  oleoresin  is  a  mild  sedative  does  not  ap- 
pear to  be  well  founded  and  is  probably  based  on  the  doubtful 
report  that  hops  ^contain  an  alkaloid  (hopeine)  resembling 
morphine  in  physiological  action.^ 

Physical  Properties 

Color:  When  spread  out  in  a  thin  layer  on  a  white  porce- 
lain surface,  the  color  of  the  oleoresin  was  observed  to  be  a 
dark  brown  resembling  very  much  that  of  the  oleoresin  of  gin- 
ger. 

Odor:  The  preparation  when  made  with  acetone  or  ether 
has  the  peculiar  odor  of  lupulin.  The  odor  of  the  commercial 
product,  however,  is  often  quite  different.  In  some  cases  it  is 
disagreeable  and  resembles  valeric  acid,^  while  in  other  cases 
it  is  pleasant  and  suggests  the  presence  of  the  ethyl  esters  of 
the  lower  fatty  acids.* 

Taste :  The  taste  is  bitter  and  somewhat  aromatic  resembling 
that  of  lupulin. 

Consistence:  The  oleoresin,  when  prepared  according  to  the 
directions  of  the  United  States  Pliarmacopoeia  of  1900  is  of  the 
consistence  of  a  very  soft  extract.  On  standing  in  partially 
filled  containers,  it  becomes  firmer  as  a  result  of  the  conversion 
of  a  part  of  the  soft  resin  into  hard  resin. 

Solubility:  The  official  preparation  is  freely  soluble  in  alco- 
hol (95  per  cent.),  acetone,  ether,  chloroform  and  glacial  acetic 
acid.  It  is  partially  soluble  in  petroleum  ether,  the  extent  of 
its  solubility  depending  on  the  age  of  the  oleoresin  (if  stored 
in  partially  filled  containers)  or  on  the  age  of  the  drug  from 
which  the  latter  is  prepared.^  It  is  also  slightly  soluble  in 
hot  water  to  which  it  imparts  a  bitter  taste. 


» Potter,  Mat.  Med.,  Pharm.  &  Therap.   (1903),  p.  339. 

«Pharm.  Ztg.   (1885),  30,  p.  620. 

•This  is  due  to  the  use  of  old  deteriorated  drug  in  the  preparation  of  the 
oleoresin  or  to  the  storing  of  the  latter  under  improper  conditions.  See  under 
"Drug  used,  its  collection,  preparation,  etc." 

♦The  agreeable  fruity  odor  sometimes  noticed  is  thought  to  be  due  to  the 
presence  of  ethyl  esters  of  the  lower  fatty  acids  formed  as  a  result  of  the 
extraction  of  old  deterloratd  drug  with  alcohol. 

•  On  aging  under  ordinary  conditions,  the  soft  resin  present  in  the  drug  or 
oleoresin  is  converted,  in  part,  into  hard  resin.  As  only  the  former  Is  soluble 
in  petroleum  ether,  old  oleoreslns,  or  those  prepared  from  old  drug,  are 
usually  less  soluble  in  this  solvent  than  the  preparations  freshly  made  from 
unaltered  drug.     See  under  "Drug  used,  its  collection,  preservation,   etc." 


192 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


Specific  gravity:  The  oleoresin  has  the  highest  specific 
gravity  of  any  of  the  preparations  of  this  class,  specific  grav- 
ities of  1.065  and  1.067  having  been  observed  for  the  same  when 
made  with  ether  and  acetone,  respectively.  Alcohol  yields  a  pro- 
duct of  somewhat  greater  density,  whereas  the  use  of  petroleum 
ether  gives  an  oleoresin  of  low  specific  gravity.  The  important 
factors  influencing  the  specific  gravity  of  this  oleoresin,  aside 
from  the  effect  produced  by  the  use  of  different  solvents  in  its 
preparation,  are  thought  to  be  the  condition  of  the  drug^  when 
extracted  and  the  presence  of  unevaporated  solvent  in  the 
finished  product.  The  results  obtained  in  the  examination  of 
laboratory  and  commercial  samples  are  given  in  the  following 
tables. 


Table  93 — Specific  gravities  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity 

1 

1910 

DuMez  &  Netzel 

Alcohol 

At  25°  C 
1  089 

2 

Acetone 

1.067 

3 

Ether  

1  065 

4 

Benzin 

1.037 

Table  94 — Specific  gravities  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
gravity 

1 

1916 

DuMez 

Sharp  &  Dohme 

At  25°  C 
1.065 

2 

Squibb  &  Sons 

1 .083  1 

3 

T.illv  JtrCn 

1.086 

,j 

*  The  preparation  had  a  slight  odor  of  ether. 

Refractive  index:  The  refractive  index  of  the  oleoresin,  when 
prepared  with  acetone,  was  found  to  be  1.516  at  25° C,  which 
agrees  fairly  well  with  that  obtained  for  the  sample  from  Sharp 
and  Dohme.  The  low  refractive  index  observed  for  the  sample 
from  Lilly  and  Co.  is  thought  to  be  due  to  the  presence  of  un- 


*  See  under  the  caption  "Chemistry  of  the  drug  and  oleoresin". 


OLEORESIN  OF  LUPULIN 


193 


evaporated  solvent  (probably  alcohol).  The  results  obtained 
in  the  determinations  made  in  the  laboratory  are  given  in  the 
tables  which  follow: 

Table  95 — Refractive  index  of  the  oleoresin  prepared  in  the 
laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractive 
index 

1916 

DuMez             

Acetone 

At  25°  C 
1.5163 

Table  96 — Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1 

1916 

DuMe/ 

Lilly  «fe  Co 

At  25°  C 
1.496 

2 

1.519 

Chemical  Properties.  ^^ 

Loss  in  weiglit  on  heating:  A  loss  in  weight  of  9.59  to  15.63 
per  cent,  was  observed  for  the  laboratory  preparations  when 
heated  at  110°  C.  Except  in  the  case  of  the  oleoresin  which 
contained  nnevaporated  solvent  (alcohol),  the  loss  did  not  ex- 
ceed 10.32  per  cent.  Results  of  a  similar  magnitude  were  ob- 
tained for  the  commercial  samples  examined  as  is  shown  in  the 
tables  which  follow. 


Table  97 — Laboratory  preparations — loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent,  of 
of  loss  on 
heating 

1 

1916 

DuMez 

Alcohol 

At  110°  C 

15. 63^ 

9.59 

10.32 

10.08 

2 

3 

" 

Ether 

4 

" 

^  Contained  unevaporated  solvent. 


194 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table   98 — Commercial  oleoresins — loss  in  weight  on  heating. 


Sample 

No. 

Date 

Observer 

Source 

Per  cent, 
of  loss  on 
heating 

1 

1916 

DuMez 

Sharp  &  Dohme 

Squibb  &  Sous 

At  110°  C 
7  22 

2 

9  46 

s 

" 

Lilly  «fe  Co 

20  68 

*  Contained  ether. 

'Probably  contained  unevaporated  solvent  (alcohol). 


Ash  content:  The  ash  contents,  in  the  case  of  the  oleoresins 
prepared  in  the  laboratory,  were  found  to  be  0.93,  1.46  and  1.82, 
depending  on  whether  ether,  acetone  or  alcohol  was  employed 
in  their  preparation.  A  somewhat  similar  variation  in  the 
amount  of  ash  obtained  for  the  commercial  samples  examined 
is,  therefore,  taken  to  be  an  indication  of  the  indiscriminate  use 
of  the  above  mentioned  solvents  in  their  manufacture,  instead 
of  acetone  as  was  directed  to  be  employed  by  the  1900  edition 
of  the  United  States  Pyiarmacopoeia.  The  slightly  higher  values 
obtained  for  the  commercial  samples  may  have  been  due  to  the 
copper,  which  was  found  to  be  present  in  considerable  amounts. 
The  results  obtained  in  the  ash  determinations  made  in  the  lab- 
oratory follow: 

Table  99 — Ash  contents  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent, 
of  ash 

1  

1916 

IVuMez 

Alcohol 

1  62 

2 

Acetone 

1.46 

8 

»' 

Ether  

0.93 

}:.!...:.. 

ti 

Petrol,  ether 

0.08 



Table  100 — Ash  contents  of  commercial  oleoresins. 


Sample 
No. 

Date 

Ob- 
server 

Source 

Percent, 
of  ash 

Forelg-n  con- 
stituents 

1 

1916 

DuMez. 

Squibb  &  Sons 

0.871 
1.53' 
1.71 

Copper 

2 

Lilly  &  Co 

3 

Sharp  &  Dohme 

1. 

» Contained  ether, 

'Probably  contained  unevaporated  solvent   (alcohol), 


OLEORESIN  OF  LUPULIN 


195 


Acid  nuynher:  The  acid  numbers  given  in  the  first  of  the 
tables  which  follow  are  those  obtained  for  preparations  which, 
had  stood  in  the  laboratory  for  six  years  previous  to  being 
examined.  As  the  acidity  of  the  oleoresin  very  likely  in- 
creases on  ageing,  when  kept  under  ordinary  conditions,  due  to 
the  oxidation  of  some  of  its  constituents,  it  is  thought  that  a 
somewhat  lower  value  is  to  be  expected  for  this  constant  in  the 
case  of  the  freshly  made  preparation.  The  relatively  low 
value  found  for  the  oleoresin  prepared  with  alcohol  was  due  to 
the  presence  of  unevaporated  solvent,  w^hich  not  only  acts  as  a 
diluent,  but  also  combines  to  some  extent  with  the  acids  present 
forming  esters,  the  latter  imparting  a  fruity  odor  to  the 
preparation.  Viewed  in  the  light  of  the  foregoing  statements, 
the  acid  numbers  obtained  for  the  commercial  samples  indicate 
that  two  of  them  were  very  probably  old  preparations  and  that 
the  third  (the  sample  obtained  from  Lilly  &  Co.)  contained 
unevaporated  solvent  (alcohol).  The  results  obtained  in  the 
determination  of  this  constant  in  the  laboratory  follow. 

Table  101 — Acid  numbers  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Acid 
number 

J 

1916 

DuMez 

Alcohol 

62.9  > 

2 

Acetone 

84  1 

3 

.,       

Ether 

Benzin 

80.1 

4 

79  7 

*  Contained  unevaporated  solvent. 

Table  102 — Acid  numbers  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Acid 
number 

1 

1916 

DuMez 

Lillv&  Co 

61.7 

2 

85.5 

3 

" 

.*Quibb&Sons 

78  4' 

*  Contained  ether. 


Saponification  value:  Saponification  values  ranging  from 
223.4  to  239.6  were  obtained  for  the  oleoresins  prepared  in  the 
laboratory,  the  variation  being  due,  very  likely,  to  the  nature  of 
the  solvent  employed  in  extracting  the  drug.     The  values  found 


196 


DU  MEZ— THE  GALENICAL  OLEORESINS 


for  the  commercial  preparations  were  somewhat  lower,  due,  in 
two  eases,  to  the  presence  of  unevaporated  solvent.  In  the  third 
instance,  the  low  saponification  value  obtained  was  very  probably 
due  to  a  difference  in  the  quality  of  the  lupulin  from  which  the 
oleoresin  was  extracted.  The  results  obtained  in  the  examina- 
tion of  laboratory  and  commercial  preparations  follow. 


Table  103 — Saponification  values  of  oleoresins  prepared  in  the 
laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Saponifica- 
tion value 

1 

1916 

DuMez 

223.4  > 

2 

Acetone . 

239  6 

3 

'« 

Ether 

230  8 

4 

•» 

Benzin 

227  4 

1  Contained  ether. 


Table  104 — Saponification  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

1 

1916 

DuMez 

Lilly  &  Co 

158. 8* 

2 

220.0 

3 

•• 

Squibb  &  Sons 

223.3" 

2  Probably   contained  unevaporated  solvent    (alcohol). 
*  Contained  ether. 


Iodine  value:  The  oleoresin,  when  prepared  with  acetone, 
ether,  or  benzin,  was  found  to  have  an  iodine  value  varying 
from  94.7  to  96.2.  When  alcohol  was  the  solvent  employed 
in  its  preparation,  the  value  obtained  was  considerably  lower, 
namely,  82.05.  A  comparison  of  thse  values  with  those  found 
for  the  commercial  samples  indicates  that  alcohol  is  sometimes 
used  in  their  preparation.  The  extrernely  low  value  obtained 
for  the  oleoresin  of  Lilly  &  Co.  is  to  be  attributed  to  the  pres- 
ence of  unevaporated  solvent  (alcohol)  as  well  as  to  the  effect 
produced  by  its  use  as  a  menstruum.  The  iodine  values  ob- 
tained for  the  preparations  examined  in  the  laboratory  are 
given  in  tihe  tables  which  follow. 


OLEORESIN  OF  PARSLEY  FRUIT 


197 


Table  105 — Iodine  values  of  oleoresins  prepared  in  the  laboratory. 


9 ana  pie 
No. 

Date 

Observer 

Solvent 

Iodine, 
value 

1... 

1916 

DuAIez       .                 

Alcohol        

82.05' 

2 

Acetone 

96.2 

3 

•' 

Ether 

94.7 

4 

" 

Benzin., 

95.7 

Alcohol  was  present. 


Table  106 — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Iodine 
value 

J 

1916 

DuMe/ 

Lilly  <fe  Co 

Sh!\rp  &  Dohme 

68.71 

2 

92.9 

3 

" 

91. S'' 

>  Alcohol  was  probably  present. 
'  The  odor  of  ether  was  noticeable. 


Adulterations, 

Adulteration  effected  through  the  use  of  old  deteriorated  drug 
in  the  iiiaimfacture  of  this  preparation  has  been  noted.  See 
under  ''Drug  used,  its  collection,  preservation,  etc." 

The  presence  of  copper  was  detected  in  all  of  the  commercial 
samples  examined.       See  under  "Ash  content." 


OLEORESIN  OF  PARSLEY  FRUIT 

Synonyms 

Aetherisches  PetersilieextraTct.  Culbreth,  Mat.  Med.   (1917),  p.  42S. 

Green  Apiol,"-  Brit.   Pharm.   Cod.   1907. 

Oil  of  Parsley,  Parrish.  Treat,  on  Phar.   (1867),  p.  757. 

Oleoresina  Petroselini,  U.  S.  P.  1910. 

Oleoresine  de  Persil,  Culbreth,  Mat.  Med.  (1917),  p.  428. 

Liquid  Apiol,  Brit.  Phann.  Cod.  1907. 


*  "Green  apiol"  is  stated  to  be  an  alcoholic  extract  of  the  parsley  fruit ; 
"yellow  apiol."  the  product  obtained  on  treating-  this  extract  with  animal 
charcoal,  or  upon  saponifying  the  same  with  lead  oxide ;  and  "white  apiol" 
the  volatile  oil  obtained  on  distilling  the  extract  with  steam.  Brit,  and 
Col.  Drugg.   (1910),  58,  p.  235. 

The  compound,  Cj^Hj^O^,  spoken  of  in  chemical  literature  as  apiol  is  known 
commercially  as  crystalline  apiol.     Brit.  Fharm.  Cod.    (1907),  p.  112. 


198  I^U  MEZ— THE  GALENICAL  OLEORESINS 

History. 

The  oleoresin  of  parsley  appears  to  have  come  into  existence 
through  the  attempts  which  were  made  to  discover  a  simple 
method  for  the  preparation  of  the  so-called  ''apiol"  of  Homolle 
and  Joret,^  which  was  first  brought  to  the  attention  of  the  phar- 
macist in  1855.  The  first  mention  of  the  oleoresin,  insofar  as 
could  be  determined  with  the  information  at  hand,  is  to  be 
found  in  Parrish's  Treatise  on  Pharmacy  published  in  1867. 
Since  that  time,  the  preparation,  or  one  of  a  similar  nature,  has 
been  on  the  market  under  the  name  of  "green  apiol"  or  ''liquid 
apiol,''  but  was  never  given  official  recognition  until  the  ap- 
pearance of  the  present  edition  of  the  United  States  PJiar- 
macopoeia. 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

In  the  present  edition  of  the  United  States  Pharmacopoeia, 
parsley  fruit  is  defined  as  follows:  ''The  dried  ripe  fruit  of 
Petroselinum  sativum  Hoffman  (Fam.  Umhelliferae),  without 
the  presence  or  admixture  of  more  than  5  per  cent,  of  foreign 
seeds  or  other  matter.  Preserve  Parsley  Fruit  carefully  in 
tightly-closed  containers  protected  from  light."  The  plant 
from  which  the  fruit  is  obtained  has  also  been  known  under  the 
following  botanical  synonyms:  Carum  Petroselinum  Benth. 
and  Hook.,  and  Apium  Petroselinum  Linne. 

Parsley  is  an  annual  herb  commonly  cultivated  in  the  gar- 
dens of  Europe  and  America.  The  fruit  ripens  in  the  fall, 
when  it  is  gathered,  dried  and  preserved  for  domestic  use  or 
shipped  to  market.  The  fruit  as  found  in  the  market  shows 
no  marked  difference  in  appearance  regardless  of  its  source. 
However,  it  is  known  to  differ  in  its  chemical  composition.  Thus, 
the  fruits  grown  in  Germany  contain  apiol  as  the  principal 
constituent  of  therapeutic  importance,  whereas,  those  grown 
in  France  contain  mj-risticin.^  The  volatile  oil  content  also 
appears  to  vary  with  the  source  as  Flueckiger^  states  that  the 


^  The  "apiol"  of  Homolle  and  Joret  is  stated  to  be  the  product  which  re- 
mains unsaponified  when  the  ether  or  chloroform  soluble  portion  of  the  alco- 
holic extract  of  parsley  fruit  is  heated  with  litharge.  Journ.  de  Pharm.  et 
de  Chim.    (1855),  28,  p.  212. 

2  See  under  "Chemistry  of  parsley  fruit". 
*  Pharmakognosie  des  Pflanzenreichs   (1891),  p.  938. 


OLEORESIN  OF  PARSLEY  FRUIT  199 

fruits  grown  in  Norway  have  an  exceptionally  strong  odor. 
Both  of  the  foregoing  variations  in  the  composition  of  the  drug 
would  naturally  be  imparted  in  an  increased  degree  to  the 
oleoresins  prepared  therefrom.  As  the  chemistry  of  the 
American  fruit  does  not  appear  to  have  been  studied,  its  value 
in  this  connection  cannot  be  said  to  be  definitely  established. 
There  is  good  reason,  however,  to  believe  that  the  oleoresins 
made  in  this  country,  in  part  at  least,  are  prepared  from  home 
grown  fruits.^ 

The  large  amount  of  fixed  and  volatile  oils  present  in  these 
fruits  requires  that  they  be  preserved  in  tightly  closed  con- 
tainers protected  from  the  light. 

Z7.  S.  P.  Text  and  Comments  Thereon, 

The  oleoresin  was  given  official  recognition  for  the  first  time 
by  being  admitted  to  the  late  edition  of  the  United  States  Phar- 
macopoeia (edition  of  1910). 

1910 

Oleoresina  Petroselini 
Oleoresin  of  Parsley  Fruit 
Oleores.  Petrosel. — Liquid  Apiol 
Parsley     Fruit,*    in  No.  60  powder,'   tillation  on  a  water-bath,*  and,  hav 
five  hundred  grammes  ....500  Gm.  ing  transferred  the  residue  to  a  dish. 
Ether,'  a  sufflcient  quantity.  remove  the  remaining  ether  by  spon 

Place  the  parsley  fruit  in  a  cylin-  taneous  evaporation  in  a  warm  place 
drical  glass  percolator  provided  with  a  stirring  frequently.'  Allow  the  oleo 
stop-cock  and  arranged  with  a  cover  resin  to  stand  without  agitation  for 
and  a  receptacle  suitable  for  volatile  four  or  five  days,  decant  the  clear 
liquids.*  Pack  the  powder  firmly,  liquid  portion  from  any  solid  residue,' 
and  percolate  slowly  with  ether,  and  preserve  it  in  well-stoppered  bot- 
added  in  successive  portions  until  the    ties.' 

drug     is     exhausted."       Eecover     the       Average    Dose. — Metric,     0.5  mil — 
greater  portion   of  the   ether  by  dis-    Apothecaries,  8  minims. 

1)  For  a  description  of  the  drug,  see  page  1104  under  *'Drug 
used,  its  collection,  preservation,  etc.'' 

2)  The  Pharmacopoeia  directs  that  the  fruit  be  reduced  to  a 


^  Joseph  K.  Janks  in  his  book  on  spices  states  thati  parsley  is  being  grown  in  thli 
country.    Jos.  K.  Janks,  Spices,  New  York  (1915),  p.  69. 

Oulbreth  on  page  428  of  the  1917  edition  of  his  work  on  Materia  Medica  also  refen 
to  the  cultivation  of  parsley  in  the  United  States. 


2Q(^  DU  MEZ— THE  GALENICAL  OLEORESINS 

No.  60  power  for  percolation.  Owing  to  the  large  fatty  oil 
content,  this  degree  of  fineness  is  difficult  to  attain,  and,  as 
experiments  conducted  in  the  laboratory  indicate  that  a  No. 
40  powder  is  equally  satisfactory  for  this  purpose,  it  appears 
that  a  change  to  this  effect  in  the  pharmacopooeial  directions 
is  desirable. 

3)  Ether  is  the  solvent  directed  by  the  Pharmacopoeia  to  be 
used  for  the  extraction  of  the  substances  constituting  the  oleo- 
resin.  Observations  made  in  the  laboratory  indicate  that 
other  solvents  may  also  be  employed  for  this  purpose  without 
in  any  way  detracting  from  the  value  of  the  finished  product. 
Thus,  acetone  and  petroleum  ether  were  found  to  yield  pro- 
ducts almost  identical  with  that  obtained  by  the  use  of  ether. 
The  latter  is  to  be  preferred  to  benzin  as  suggested  by  Bering- 
er  (1892)  since  its  composition  is  more  constant.  Alcohol 
which  is  used  commercially  in  the  preparation  of  some  of  the 
so-called  liquid  apiols  dissolves  a  considerable  amount  of  col- 
oring matter  and  other  inert  substances  and,  therefore,  yields 
a  product  of  inferior  quality. 

4)  For  a  description  of  the  various  forms  of  percolators  which 
have  been  designed  to  meet  the  specifications  of  the  Pharma- 
copoeia, see  Part  I  under  "Apparatus  used". 

5)  The  pharmacopoeial  directions  governing  the  extraction  of 
the  oleoresinous  material  are  to  slowly  percolate  the  drug  with 
ether,  added  in  successive  portions,  until  complete  exhaustion 
has  been  effected.  Here  again,  the  use  of  some  form  of  contin- 
uous extraction  apparatus  would  appear  to  be  an  improve- 
ment over  the  present  method. 

6-7)  For  comments  on  this  step  in  the  pharmacopoeial  method 
of  preparation,  see  under  comments  on  the  oleoresin  of  cubeb. 

8)  Upon  the  complete  removal  of  the  solvent  from  the  perco- 
late, the  residual  oily  liquid  deposits  a  small  amount  of  waxy 
matter  which  the  Pharmacopoeia  directs  shall  be  removed  by 
decantation.  When  either  is  the  solvent  used  in  extracting 
the  drug,  this  deposit  amounts  to  less  than  1  per  cent  of  the 
oleoresin,  while  the  percentage  is  somewhat  greater,  about  1.5 
per  cent  when  acetone  is  used.  The  deposit  resulting  when 
benzin  was  the  solvent  employed  was  found  by  Beringer  to  be 
equal  to  about  3  per  cent. 

9)  The  oleoresin  should  be  kept  in  well-stoppered  bottles  as 


OLEORESIN  OF  PARSLEY  FRUIT 


201 


it  loses  volatile  oil  upon  exposure  to  the  air,  and  as  the  glycer- 
ides  are  prone  to  undergo  partial  decomposition  due  to  the  ac- 
tion of  the  moisture  and  oxygen. 


Yield. 

The  information  at  hand  is  not  sufficient  to  permit  of  a  state- 
ment being  made  as  to  what  the  average  yield  of  oleoresin 
should  be  in  this  case.  The  results  obtained  in  the  laboratory 
and  those  reported  by  Beringer  show  that  it  is  at  least  24  per 
cent.,  when  ether  or  acetone  are  the  solvents  employed  in  ex- 
tracting the  drug,  whereas  those  reported  by  Vanderkleed 
would  appear  to  indicate  that  the  yield  is  much  lower.  The 
available  information  of  this  nature  is  given  in  the  following 
tables : 

Table  107 — Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  Oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other  Solvents 

Remarks 

1892.. 

Beringer 

Per 
cent. 

Per 
cent. 

24.0 

Per 
cent. 

Per  cent. 

Benzin 
19.3 

Solvent  (?) 
11.40 

13.04 
14.70 

The  total  yield  of 

1913 

Vanderkleed   . . . 

extractive    mat- 
ter to   benzin  is 
given  as  22.3  per 
cent,    which  in- 
cludes 3  percent, 
of  deposited  wax. 

Reported  as  yield 

of  oleoresin. 

" 

Table  108 — Yield  of  oleoresin  as  obtained  in  the  laboratory. 


Observer 

Yield  of  oleoresin  to— 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other 
•  sol- 
vents 

Remarks 

1916 

DuMez 

Per  ct. 

Perct. 

28.89 

Perct, 
29.17 

Perct. 

Represents  the  yield  using  a 

Soxhlet's  Extraction   App. 

2Q2  DU  MEZ— THE  GALENICAL.  OLEORESINS 

Chemistry  of  the  Drug  and  Oleoresin. 
Enumeration  of  Constituents. 

The  following  are  the  known  constituents  of  parsley  fruit  which 
may  be  considered  of  pharmaceutical  interest ;  volatile  oil,  fatty 
oil,  apiin,  and  inorganic  substances.  While  analyses  of  the 
oleoresin  have  not  been  reported,  the  first  two  named  constitu- 
ents of  the  fruit,  together  with  a  small  amount  of  inorganic 
matter,  very  likely  represent  this  preparation  when  made  by 
extracting  the  drug  with  ether,  as  apiin  is  stated  to  be  insoluble 
in  this  solvent. 

Occurrence  and  Description  of  Individual  Constituents. 

Volatile  Oil}  The  volatile  oil  of  parsley  fruit  is  described  as  a 
colorless  or  yellowish,  thick  liquid  having  a  specific  gravity  of 
1.03  to  1.10  at  15  °C.  The  angle  of  rotation  in  a  100  milli- 
meter tube  is  given  as  -5°  to  -10°.  It  is  soluble  in  alcohol,  ether, 
chloroform  and  petroleum  ether.  On  cooling  or  shaking  with 
water,  it  precipitates  apiol.^ 

The  composition  of  the  oil  varies  with  the  locality  in  which 
the  fruit  is  grown.  The  principal  constituent  of  the  oil  dis- 
tilled from  the  fruit  grown  in  Germany  is  apiol.  Myristicin 
is  present  only  in  very  small  quantities.'  It  is  stated  that  the 
apiol  content  is  often  so  great  that  the  oil  is  a  semi-solid  at  or- 
dinary temperatures.  In  the  French  oil,  myristicin  predom- 
inates, while  apiol,  together  with  allyltetramethoxybenzene,  is 
present  in  small  amount.*  The  constitution  of  these  compounds 
is  represented  by  the  following  formulas: 


*The  following-  list  comprises  the  more  important  references  to  the  earlier 
literature  on  the  volatile  oil:  Bley,  TrommsdorfC's  neues  Joum.  (1827),  14, 
p.  134;  Bolle,  Arch,  der  Pharm.  (1829),  29,  p.  168;  Blanchet  and  Sell,  Ann. 
der  Chem.  (1833),  6,  p.  301;  Loewig  and  W^eidmann,  Ibid.  (1839),  32,  p. 
283;  von  Gerichten,  Ber.  der.  deutsch.  chem.  Ges.  (1876),  9,  pp.  258  and 
1477. 

aSchimmel  &  Co.,  Ber.    (1906),  p.  95. 

"Thorns,  Ber.  der  deutsch.  chem.  Ges.  (1903),  36,  p.  3451;  Ihid  (1908), 
41,  p.  2753;  Chevalier,  Bull.  sci.  pharmacologique  (1910),  17,  p.  128;  Chem. 
Abs.    (1911).  5,  p.  1490. 

*Ibid.     Also,   Bignami  and  Testoni,   Gaz.   Chim.   ital.    (1900),   30,  p.    240. 


OLEORESIN  OF  PARSLEY  FRUIT 


203 


Apiol  is  a  crystalline  solid  possessing  in  a  strong  degree  the 
odor  of  parsley.  Its  melting  point  is  30 °C  and  the  boiling 
point  294°  C*  Eykman^  gives  the  specific  gravity  at  14°  C  as 
1.176,  and  the  refractive  index  [n]D  as  1.538.  It  is  soluble  in 
alcohol,  ether,  chloroform  and  oils.  It  also  dissolves  in  con- 
centrated sulphuric  acid,  the  solutron  formed  being  blood-red 
in  color. 

Myristicin  is  a  liquid  possessing  but  little  odor.  It  does  not 
solidify  even  when  cooled  to  a  comparatively  low  temperature. 
Semmler^^  gives  the  specific  gravity  as  1.141  at  25° C.  Its 
solubility  is  similar  to  that  of  apiol. 

In  addition  to  the  foregoing,  Thoms^^  reports  the  presence 
of  the  following  in  both,  the  German  and  French  oils :  1-pinene, 
phenols  and  palmitic  acid. 

Semmler^^  reports  the  volatile  oil  content  of  parsley  fruit 
to  be  2  to  6  per  cent. 

Fatty  X)il}^  The  fatty  oil  of  parsley  fruit  is  a  greenish  yellow 
mobile  liquid.  It  is  soluble  in  a  mixture  of  alcohol  and  ether, 
in  ether,  chloroform  and  carbon  disulphide.  A  sample  from 
Schimmel  &  Co.,  examined  by  von  Gerichten  and  Koehler,^* 


'Eykman,  Ber.  der.  deutsch.  chem.  Ges.  (1890),  23,  p.  862;  Thorns,  IMd. 
1903,  36,  p.   174. 

•Thorns.   Chem.   Ztg.    (1903).   27,  p.   938. 

T  Thorns.  Ber.  der.  deutsch.  chem.   Ges.    (1908),  41,   p.    2761. 

•Ciamician  and  Silber,  IJyid.    (1888),   21,  p.  1632. 

•I.   c. 

»»Semmler,  Die  aetherische  Oele   (1907).  4.  p.  168. 

^  Arbeiten  axis  d.  Pharm.  Inst.,   Univ.  Berlin    (1909),   6,  p.   190. 

"  Semmler,  Die  aetherische  Oele   (1907),  4.  p.  173. 

"  Grimme  obtained  16.7  per  cent,  of  a  red-brown  oil  having  the  following 
properties:  specific  gravity  at  15°  C,  0.9243  ;  refractive  index  at  35"  C,  1.4778  ; 
saponification  value,  176.5  ;  iodine  value,  109.6  ;  acid  value,  3.4  ;  unsaponifl- 
able  matter,  2.18  per  cent.  He  was  unable  to  obtain  a  test  for  the  presence 
of  phytosterin  in  the  unsaponifiable  residue.  Pharm,  Centralh.  (1911),  52, 
p.   663. 

"Ber.  der.  deutsch.  chem.  Ges.    (1909),  42.  p.  1638. 


204  ^U  MEZ— THE  GALENICAL  OLEORESINS 

showed  the  following  properties:  specific  gravity  at  15°C,  0.972; 
refractive  index  at  40°C,  1.4624;  saponification  value,  190.9; 
iodine  value,  80.07. 

The  saponifiable  portion  of  the  oil  was  found  to  be  com- 
posed of  the  glyceryl  esters  of  oleic,  palmitic,  stearic  and 
petroselinic  acids.  The  latter  is  stated  to  be  isomeric  with 
oleic  acid.  From  the  unsaponifiable  residue,  Matthes  and 
Heintz^^  isolated  a  hydrocarbon,  C20H40,  to  which  they  gave  the 
name  petrosilan;  also,  myricyl  alcohol  and  a  mixture  giving  a 
test  for  phytosterin. 

The  average  fatty  oil  content  of  the  fruit  is  probably  about 
20  per  cent.^^ 

Apiin.^'^  Apiin  (C27H30O1G)  is  a  glucoside.  Its  melting 
point  is  stated  to  be  228  °C.  On  hydrolysis,  it  yields  a  sugar 
and  apigenin  (trioxyflavon)  C15H10O5.  It  is  soluble  in  hot 
alcohol  or  water,  insoluble  in  ether,  and  therefore,  it  is  not 
likely  to  be  present  in  the  oleoresin. 

Ash.  Available  information  concerning  the  constituents  of 
the  ash  of  parsley  fruit  is  limited  to  the  anaylsis  of  Rump,^* 
who  reports  the  presence  of  the  basic  elements,  K  Ca,  Mg  and 
Fe  in  combination  with  the  acids,  HCl,  H2SO4,  H3PO4,  H2CO3 
and  H2Si03,  also,  some  free  SiOo. 

The  ash  content^®  of  parsley  fruit  is  about  6.50  to  7.00  per 
cent.  Commercial  samples  sometimes  show  a  higher  percentage 
of  ash  due  to  contamination  with  foreign  matter.-^ 

Constituents  of  Therapeutic  Importance. 

The  oleoresin  of  parsley  fruit  is  said  to  be  used  chiefly  as  an 
emmenagogue.  Such  being  the  case,  its  therapeutical  value 
is  undoubtedly  due  to  the  volatile  oil  which  it  contains  as  both 
apioP   and  myristicin,-   constituents  of  the  essential  oil,  have 


i^Ber.  der.  pharm.  Ges.  (1909),  19,  p.  325. 

1^  Rump,  obtained  22  per  cent,  of  fatty  oil.  Buchner's  Repert.  f.  d.  Fharm. 
(1836),  6,  p.  6.     Grimme  gives  the  yield  as  16.7   per  cent.  1.  c. 

"von  Gerichten,  Ber.  der  deutsoh.  chem.   Ges.    (1876),   9,  p.    1121. 

"Buchner's  Repert.  f.   d.  Pharm.    (1836),   56.   p.   26. 

1®  Rump  gives  the  ash  content  as  6.5  per  cent.  Ibid.  Warnecke  reports 
the  percentage   of  ash  as   7.04.      Pharm.   Ztg.    (1886),   31.    p.    53  6. 

*•  La  Wall  and  Bradshaw  report  two  commercial  samples  of  parsley  fruit 
yielding  6.61  and  9.10  per  cent,  of  ash,  respectively.  Proc.  A.  Ph.  A.  (1910), 
58,  p.   752. 

^Heffter,  Arch.  f.  exp.  Path.  u.  Pharmak.  (1895),  35,  p.  365.  Chevalier 
Bull.   Sci.  pharmacologique,   17,   pp.   128-131. 

2Juerss,  Schimmel  &  Co.,  Ber,    (1904),  p.  159. 


OLEORESIN  OF  PARSLEY  FRUIT 


205 


been  shown  to  be  severe  intestinal  irritants.  The  activity  of 
the  volatile  oil  may  be  further  accounted  for  by  the  presence 
of  terpenes  as  these  compounds  are  also  known  to  be  irritants.* 

PJiysical  Properties 

Color:  When  spread  out  in  a  thin  layer  on  a  while  porcelain 
surface,  the  oleoresin  was  observed  to  be  greenish-yellow  in 
color.  The  so-called  fluid  apiols  of  commerce,  preparations 
made  with  alcohol,  are  of  a  comparatively  deep  green  color. 

Odar:  The  oleoresin  has  the  agreeable  aromatic  odor  of 
parsley. 

Taste:  The  taste  is  spicy  like  that  of  the  drug  from  which 
it  is  prepared. 

Consistence:  The  oleoresin  is  a  rather  thin  liquid,  being  of 
about  the  consistence  of  olive  oil. 

Solubility:  The  official  preparation  is  soluble  in  acetone, 
ether,  chloroform,  carbon  disulphide  and  petroleum  ether.  It 
is  almost  insoluble  in  alcohol  or  water. 

Specific  gravity:  The  specific  gravities  of  the  oleoresins  pre- 
pared in  the  laboratory  were  found  to  be  0.937  and  0.940  at  25° C. 
In  the  making  of  these  preparations  ether  and  acetone,  respec- 
tively, were  employed  as  menstrua  for  extracting  the  drug.  The 
specific  gravity  of  the  only  commercial  sample,  conforming  in  its 
general  properties  to  the  official  product,  was  observed  to  be 
about  the  same,  i.  e.  0.943.  In  the  case  of  the  other  commercial 
products,  the  greater  density  is  thought  to  be  due  to  the  use  of 
alcohol  in  their  preparation.^  The  results  for  the  determina- 
tions made  in  the  laboratory  follow. 

Table  109 — Specific  gravities  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

specific 
gravity 

I 

1916 

Du  Me7             

Acetone 

At25°  C 
0.940 

2 

Ether 

0.937 

sKehrer,    Arch.  f.    Gyn.    (1910),    90.   p.    169. 

^  This  statement  is  also  based  on  the  dark  green  color  of  the  preparations 
and  the  fact  that  alcohol  is  the  solvent  mentiond  in  the  literature  in  con- 
nection with  the  preparation  of  the  so-called  fluid  apiols.  See  under  "His- 
tory" of  the  oleoresin. 


206 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  110 — Specific  gravities  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Specific 
erravity 

1 

1916 

DuMez 

Sharp  &  Dohme 

At  25°  C 
0.943 

2 

SQuibb  &  Sons 

0.984' 

3 

" 

Merck&  Co 

1.0082 

^Apiol,  fluid, — Squibb. 

2  Apiol,  fluid,  green, — Merck. 


Refractive  index:  Observations  made  in  the  laboratory  in- 
dicate that  the  oleoresin  should  have  a  refractive  index  of 
about  1.477  at  25° C,  when  ether  or  acetone  are  employed  in  the 
extraction  of  the  drug.  A  result  almost  identical  with  the 
preceding  was  obtained  for  the  only  commercial  sample  ex- 
amined. The  refractive  indices  observed  in  the  case  of  the 
so-called  liquid  apiols  were  somewhat  higher,  due  very  likely 
to  the  use  of  alcohol  in  their  preparation.  The  data  given  in 
the  following  tables  illustrate  these  points. 

Table  111 — Refractive  indices  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractlre 
index 

1 

1916 

DuMez 

Acetone 

At  25°  C 

1  477 

2 

Ether 

1.477 

Table  112 — Refractive  indices  of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Refractive 
index 

1 

1916 

DuMez 

Sharp  &  Dohme 

At  25°  C 
1.475 

2 

Sauibb  &  Sons 

1  486' 

3 

♦• 

Merck  &  Co 

1  1488* 

1  Apiol,  Fluid— Squibb. 

*  Apiol,  Fluid,  Green, — Merck. 


OLEORESIN  OF  PARSLEY  FRUIT 


207 


Ckemical  Properties. 

Loss  in  weight  on  heating:  The  oleoresins  prepared  in  the 
laboratory,  using  ether  and  acetone  as  menstrua  for  exhausting 
the  drug,  lost  7.87  and  7.92  per  cent,  of  their  weight,  respec- 
tively, on  heating  at  110°C.  In  the  case  of  the  only  com- 
mercial sample  examined,  the  loss  was  about  one-half  as 
great  due  very  likely  to  a  smaller  amount  of  volatile  matter 
(essential  oil)  being  contained  in  the  drug  from  which  the  lat- 
ter was  prepared.  The  results  obtained  are  given  in  the 
tables  which  follow. 


Table  113 — Laboratory  preparations — loss  in  weight  on  heating. 


Sample 
No. 


Date 


1916 


Observer 


DuMez 


Solvent 


Acetone 
Ether... 


Percent,  of 
loss  on 
heatlncr 


At  100°  C 
7.92 
7.87 


Table  114 — Commercial  oleoresins — loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent,  of 
loss  on 
heating 

1 

1916 

DuMez 

Sharp  &  Dohme 

At  110°  C 
8.35 

Asli  content:  The  results  obtained  in  the  determination  of 
the  ash  content  of  the  oleoresins  examined  in  the  laboratory  are 
given  in  the  tables  which  follow.  Aside  from  the  fact  that  the 
amount  of  ash  obtained  varied  with  the  solvent  used  in  the 
making  of  the  preparations,  the  only  items  of  importance 
brought  out  by  these  results  are  that  ether  was  evidently  em- 
ployed in  the  manufacture  of  the  commercial  product  and  that 
the  latter  contained  copper. 

Table  115 — Ash  contents  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent, 
of  ash 

1 

1916 

DuMez 

0.18 
0.09 

2 

F.thAT 

208 


DU  MEZ— THE  GALENICAL,  OLEORESINS 


Table  116 — Ash  contents  of  commercial  oleoresins. 


Sample 
NO. 

Date 

Observer 

Source 

Percent, 
of  ash 

Foreign  con- 
stituents 

1 

1916 

DuMez 

Sharp  &  Dohme 

0.09 

Copper 

Acid  number:  The  acid  numbers  obtained  for  the  oleoresins 
prepared  with  acetone  and  ether  were  found  to  be  9.3  and  9.2, 
respectively,  indicating  that  the  difference  in  the  nature  of  the 
two  solvents  has  but  little  influence  on  the  value  of  this  con- 
stant. The  high  value  found  for  the  sample  obtained  from 
Sharp  &  Dohme  is  thought  to  be  due  to  the  hydrolysis  of  some 
of  the  glycerides,  and,  therefore,  to  indicate  an  old  preparation, 
or  one  that  has  been  prepared  from  old  deteriorated  drug.  The 
acid  numbers  obtained  for  the  oleoresins  examined,  also  those 
found  for  the  so-called  liquid  apiols,  are  given  in  the  tables 
which  follow. 

Table  117 — Acid  numbers  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Acid 
number 

1 

1916 

DuMez 

Acetone 

9  3 

2 

Ether 

9.2 

Table   118 — Acid   numbers   of  commercial  preparations. 


Sample 
No. 

Date: 

Observer 

Source 

Acid 
number 

I 

1916 

DuMez                

Merck  &  Co 

12.11 

2 

Sharp  &  Dohme 

50.5 

3 

n 

Squibb  &  Sons 

58.5' 

^Apiol,  Fluid,  Green. 


Saponification  value:  The  saponification  values  of  the  oleo- 
resins prepared  in  the  laboratory,  using  ether  and  acetone  as 
menstrua  for  extracting  the  drug,  were  found  to  be  158.5  and 
165.6,  respectively.      The  high  value  (181.6)  obtained  for  Sharp 


OLEORESIN  OF  PARSLEY  FRUIT 


209 


&  Dohme's  preparation  is  thought  to  be  due  to  the  presence  of  a 
relatively  large  amount  of  the  glyceride  of  petroselinic  acid, 
which  is  stated  by  von  Gerichten  to  have  a  saponification  value 
of  191.2.  See  under  ''Chemistry  of  the  drug  and  oleoresin." 
Tables  showing  the  saponification  values  of  the  preparations 
examined  in  the  laboratory  follow.  For  comparison  with  the 
foregoing  data,  the  values  obtained  for  the  so-called  liquid 
apiols  have  also  been  included  in  these  tables. 

Table     119 — Saponification    values    of    oleoresins    prepared    in    the 

laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Saponi6ca- 
tion  value 

1 

1916 

DuMez  

Acetone 

165  6 

2 

Ether 

158.5 

Table  120 — Saponification  values  of  commercial  preparations. 


Sample 

No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

I 

1916 

DuMez 

Mpfck  &Co 

108.51 

S::::::::: 

Sauibb  &  Sons 

126.7''' 

45 

" 

Sharp  &  Dohme 

181.6 

^  Apiol,  Fluid,  Green, — Merck. 
2Apiol,  Fluid,— Squibb. 


Iodine  value:  The  iodine  values  as  found  for  the  oleoresins 
prepared  in  the  laboratory  are  given  in  the  first  of  the  tables 
which  follow.  It  will  be  observed  that  there  is  a  considerable 
difference  in  these  values  due  to  the  nature  of  the  solvent  em- 
ployed in  extracting  the  drug.  The  low  iodine  value  observed 
for  the  preparation  made  by  Sharp  &  Dohme  is  to  be  attributed 
to  the  partial  oxidation  of  the  unsaturated  glycerides.  For 
comparison,  the  iodine  values  of  two  samples  of  so-called 
^'liquid  apiols "(  preparations  made  with  alcohol)  have  been 
included  in  the  tables  which  follow. 


210 


DU  MEZ— THE  GALENICAL  OLBORESINS 


Table  121 — Iodine  values  of  oleoresins  prepared  in  the  laJ)oratoru, 


Sample 
No. 

Date 

Observer 

Solrent 

Iodine  value 

1 

1916 

DuMez 

Acetone 

132.5 

2 

Ether 

12?. 9 

Table  122 — Iodine  values  of  commercial  preparations. 


Sample 
No. 

Date 

Observer 

Source 

Iodine  value 

1 

1916 

DuMez 

Sharp  &  Dohme 

110.6 

2 

Sfiuibb  &  Sons 

123.3  1 

3 

'»       

Merck  &  Co 

130.2  « 

1  Labeled  "Apiol-Fluid." 

2  Labeled  Apiol,  Fluid,  Green. 

Adulterations. 

A  trace  of  copper  was  found  to  be  present  in  the  commercial 
samples  examined.      See  under  "Ash  content.'' 

OLEORESIN  OF  PEPPER 

Synonyms 

Aetherisches  Pfefferextralct,  Nat.  Disp.  1884. 

Ethereal  Extract  of  Black  Pepper,  King's  Am.  Disp.  1900. 

Extractum  Piperis,  Hirsh,  Univ.  P.   1902,  No.   1244. 

Extr actum  Piperis  Fluidum,  U.  S.  P.  1850. 

Fluid  Extract  of  BlacTc  Pepper,  U.   S.  P.  1850. 

Oil  of  BlacTc  Pepper,  King's  Am.  Disp.  1900. 

Oleoresina  Piperis,  U.  S.  P.  1900. 

OUoresine  de  Poivre  noir,  U.  S.  Disp.  1907. 


History. 

The  oleoresin  of  pepper  appears  to  have  been  first  obtained 
as  a  by-product^  in  the  preparation  of  piperine.  Thus,  Dr. 
Meli  in  France  as  early  as  1825,  reported  having  obtained  the 
so-called  ''oil  of  black  pepper''  as  a  residue  on  separating  the 
piperine  from  the  alcoholic  extract  of  the  drug.  The  first 
notice  of  its  use  as  a  therapeutic  agent  apparently  came  from 

>Jourdan,  Univ.  P,  (1832),  p.  84f 


OLEORESIN  OF  PEPPER  211 

America  as  Carpenter,  in  1829,  in  an  article  on  Peruvian  bark, 
refers  to  its  use  by  Dr.  Chapman  of  Philadelphia  in  connec- 
tion with  the  administration  of  quinine.  The  oleoresin  prepared 
with  ether  became  official  in  the  United  States  Pharmacopoeia 
in  1850  under  the  title  Extractum  Piperis  Fluidum.  In  the 
1860  edition,  the  name  was  changed  to  Oleoresina  Piperis,  under 
which  title,  it  is  still  official  at  the  present  time.  Neither  this 
preparation  nor  one  of  a  similar  nature  has  ever  been  given  of- 
ficial recognition  abroad. 

Drug  Used,  Its  Collection,  Preservation,  Etc. 

According  to  the  present  edition  of  the  United  States  PJiar- 
macopoeia,  the  drug  recognized  is  ''the  dried,  unripe  fruit  of 
Piper  nigrum  Linne  (Fam.  Piperaceae),  without  the  presence 
or  admixture  of  more  than  two  per  cent  of  stems  or  other  for- 
eign matter. ' '  It  has  also  occassionally  been  referred  to  under 
the  botanical  synonyms.  Piper  trioicum  Roxb. 

As  becomes  apparent  from  the  foregoing,  only  the  unripe 
fruits  should  be  used.  As  the  fruit  reaches  maturity,  the 
chlorophyll  content  diminishes  and  it  becomes  less  pungent.* 
A  variation  in  the  chlorophyll  would  naturally  effect  the  prop- 
erties of  the  oleoresin  prepared  therefrom,  while  a  difference 
in  piperine  content  would  have  no  significance  in  this  connec- 
tion as  only  a  small  portion  of  the  total  piperine  (to  which  pep- 
per owes  its  pungency)^  remains  in  solution  in  the  oleoresin, 
the  greater  part  being  precipitated  upon  the  ermoval  of  the  sol- 
vent. 

Pepper,  as  it  occurs  on  the  market,  consists  of  a  number  of 
commercial  varieties,  viz:  Malabar,  Cochin,  Penang,  Singapore, 
Siam  and  others.^  The  quality  of  these  varieties  is  ordinarily 
governed  by  weight,  the  Malabar  being  the  heaviest.  The 
Penang,  however,  is  stated  to  be  the  most  pungent.  The  man- 
ner in  which  either  of  these  qualities  effect  the  oleoresin  does 
not  appear  to  have  been  determined.  While  the  Pharmacopoeia 
makes  no  provisions  for  the  preservation  of  this  drug,  its  volatile 
oil  content  necessitates  the  use  of  closed  containers. 


iFlueckiger,  Pharmakognosie  des  Pflanzenreiches    (1891),  p.   913. 
'Kayser,  Chem.  Centralb.    (1888),  59,  p.  261. 
■Jos.  K.  Janks,  Spices,  New  York,  (1915),  p.  10. 


-212  I^U  MEZ— THE  GALENICAL,  OLEORESINS 


JJ.  S.  p.  Text  and  Comments  Thereon. 

The  oleoresin  of  pepper  has  been  official  in  the  United  States 
Pharmacopoeia  since  1850,  when  it  was  recognized  under  the 
title  of  Extractum  Piperis  Fluidum. 


1850 

Extractum  Piperis  Fluidum 

Fluid  Extract  of  Black  Pepper 

Take    of   Black    Pepper/   in   powder,^  heat,  apint  and  a  half  of  ether,"  and 

a  pounds  expose  the  residue  in  a  shallow  ves- 

Ether,^  a  sufficient  quantity.  sel,  until  the  whole  of  the  ether  has 

Put  the  powder  into  a  percolator,*  evaporated,^     and     the     deposition  of 

and  pour  ether  gradually  upon  it  until  piperin  in  crystals,  has  ceased.  Lastly, 

two  pints  of  filtered    liquor    are  ob-  separate    the    piperin    by    expression 

tained."        From    this    distill    off,    by  through  a  cloth,*  and  keep  the  liquid 

means   of    a   water-bath,   at    a   gentle  portion. 


1860 
Oleoresina  Piperis 
Oleoresin  of  Black  Pepper 
Extractum  Piperis  Fluidum,  Pharm.,  1850 

Take  of  Black  Pepper,^  in  fine  pow-  eighteen  fluidounces  of  ether,*  and 
der,2  twelve  troyounces;  expose  the  residue,  in  a  capsule,  until 
Ether,'  a  sufficient  quantity.  the  remaining  ether  has  evaporated,^ 
Put  the  Black  Pepper  into  a  cylin-  and  the  deposition  of  piperin  in  cry- 
drical  percolator,*  press  it  firmly,  and  stals  has  ceased.  Lastly,  separate 
gradually  pour  ether  upon  it  until  the  oleoresin  from  the  piperin  by  ex- 
twenty-four  fluidounces  of  filtered  pression  through  a  muslin  strainer,' 
liquid  have  passed."  Recover  from  and  keep  it  in  a  well-stopped  bottle.' 
this,  by  distillation  on  a  water-bath. 


OLEORESIN  OF  PEPPER 


2ia 


1870 

Oleoresina  Piperis 
Oleoresin  of  Black  Pepper 


Take  of  Black  Pepper/  in  fine  pow- 
der,' twelve  troy  ounces; 

Ether,^  a  suificient  quantity. 

Put  the  Black  Pepper  into  a  cylin- 


Recover  the  greater  part  of  the  ether 
by  distillation  on  a  water-bath,*  and 
expose  the  residue,  in  a  capsule,  until 
the   remaining  ether  has  evaporated,' 


drical     percolator     provided     with   a  and  the  deposition  of  piperin  in  crys- 

stop-cock,    and    arranged   with    cover  tals  has  ceased.      Lastly,  separate  the 

and    receptacle    suitable    for    volatile  oleoresin  from  the  piperin  by  expres- 

liquids,*  press  it  firmly,  and  gradually  sion   through   a   muslin  strainer,*  and 

pour  ether  upon  it,  until  twenty  fluid  keep  it  in  a  well-stopped  bottle.' 
ounces  of  liquid  have  slowly  passed.' 

1880 

Oleoresina  Piperis 
Oleoresin  of  Pepper 
Pepper,^  in  No.  60  powder,'  one  hun-   greater  part  of  the  ether  by  distilla- 

dred  parts  100    tion  on  a  water-bath,*  and  expose  the 

Stronger  Ether,'  a  sufficient  quantity,  residue,  in  a  capsule,  until  the  re- 
Put  the  pepper  into  a  cylindrical  maining  ether  has  evaporated,'  and 
percolator,  provided  with  a  cover  and  the  deposition  of  piperine,  in  crystals, 
receptacle  suitable  for  volatile  liquids,*  has  ceased.  Lastly,  separate  the 
press  it  firmly,  and  gradually  pour  oleoresin  from  the  piperine  by  ex- 
stronger  ether  upon  it,  until  one  hun-  pression  through  a  muslin  strainer.' 
dred  and  fifty  (150)  parts  of  liquid  Keep  the  oleoresin  in  a  well-stopped 
have     slowly    passed.'      Recover    the   bottle.' 


1890 

Oleoresina  Piperis 
Oleoresin  of  Pepper 

Pepper,^  in  No.  60  powder,'  five  hun-  from  the  percolate  by  distillation  on  a 

dred  grammes 500  Gm.  water-bath,*    and,    having    transferred 

Ether,^  a  sufficient  quantity.  the  residue  to  a  capsule,  set  this  aside 

Put   the  pepper   into    a   cylindrical  until  the  remaining  ether  has  evapor- 

glass  percolator,  provided  with  a  stop-  ated,^  and  the  deposition  of  crystals  of 

cock,  and  arranged  with  a  cover  and  piperine     has     ceased.     Lastly,   sepa- 

receptaele  for  volatile  liquids.'*     Press  rate  the  oleoresin  from  the  piperin  by 

the  drug  firmly,  and  percolate  slowly  expression  through  a  muslin  strainer.' 

with    ether,   added  in    successive  por-  Keep   the  oleoresin   in   a  well-stop- 

tions,    until    the     drug  is  exhausted."  pered  bottle.' 
Recover  the  greater  part  of  the  ether 


214  E>U  MEZ— THE  GALENICAL  OLEORESINS 

1900 

Oleoresina  Piperis 
Oleoresin  of  Pepper 

Pepper/  in  No.  40  powder/  -five  hun-  distillation     on     a    water-bath,'  and, 

dred  grammes   500.    Gm.  having    transferred  the   residue    to   a 

Acetone/  a  sufficient  quantity.  dish,  set  this  aside  in  a  warm  place, 

Introduce  the  pepper  into  a  cylin-  until  the  remaining  acetone  has  evap- 

drical  glass  percolator,  provided  with  orated,''  and  the  deposition  of  crystals 

a  stop-cock,  and  arranged  with  a  cover  of  piperin  has  ceased.       Lastly,  sepa- 

and  a  receptacle  for  volatile  liquids.*  rate  the  oleoresin  from  the  piperin  by 

Pack  the  powder  firmly,  and  percolate  straining     through     purified     cotton.' 

slowly  with  acetone,  added  in  succes-  Keep  the  oleoresin  in  a  well-stoppered 

sive  portions,  until  the  pepper  is  ex-  bottle.* 

hausted."       Kecover  the  greater  part  Average  dose. — 0.030  Gm.  :=30  mil- 

of  the  acetone  from  the  percolate  by  ligrammes  (^  grain). 


1910 
Oleoresina  Piperis 
Oleoresin  of  Pepper 
Olcores.  Piper. 

Pepper,*  in  No.  40  powder,*  -five  hun-  tillation   on   a  water-bath,*   and,   hav- 

dred  grammes   500.    Gm.  ing  transferred  the  residue  to  a  dish, 

Ether,^  a  sufficient  quantity.  set  this  aside  in  a  warm  place  until 

Place    the   pepper   in    a   cylindrical  the  remaining  ether   has  evaporated,' 

glass  percolator,  provided  with  a  stop-  and  the  deposition    of    piperine    has 

cock,  and  arranged  with  a  cover  and  ceased.        Lastly,    separate    the    oleo- 

s.     receptacle     for     volatile     liquids.*  resin   from  the  piperine  by  straining 

Pack  the    powder    firmly,    and  perco-  through  purified   cotton.'       Keep   the 

late  slowly  with  ether,   added  in  sue-  oleoresin  in  a  well-stopped  bottle.' 

cessive  portions  until  the  drug  is  ex-  Average  Dose. — Metric,  0.03  Gm. — 

hausted.'     Kecover  the  greater  part  of  Apothecaries,  ^2  grain, 
the  ether  from  the  percolate  by  dis- 

1)  For  a  description  of  the  official  drug,  see  page  1117  under 
^'Drug  used,  its  collection,  preservation,  etc." 

2)  The  last  two  editions  of  the  Pharmacopoeia  have  specified 
that  the  drug  be  in  the  form  of  a  No.  40  powder  for  percolation. 
Previous  editions,  with  the  exception  of  that  of  1850,  in  which 
the  degree  of  .fineness  was  not  stated,  required  that  a  fine 


OLEORESIN  OF  PEPPER  215 

powder  (No.  60)  be  used  for  this  purpose.  The  coarser 
powder  possesses  the  advantages  of  being  more  readily  pro- 
duced and  of  being  better  adapted  to  the  rapid  exhaustion  of 
the  drug. 

3)  The  solvents  which  have  been  experimented- with  in  the 
preparation  of  this  oleoresin  are  alcohol,  ether,  acetone,  ben- 
zin  and  petroleum  ether.  Of  these,  ether  has  proven  to  be  the 
most  satisfactory  and  is  the  solvent  specified  for  this  purpose 
by  the  present  Pharmacopoeia.  Acetone,  which  was  directed 
to  be  used  by  the  Pharmacopoeia  of  1900,  like  alcohol,  is  un- 
satisfactory as  the  large  amount  of  extractive  matter  obtained 
interferes  with  the  separation  of  the  piperine.  Benzin  or  pe- 
troleum ether,  on  the  other  hand,  dissolves  piperine  but 
slightly  and,  therefore,  yield  a  product  low  in  piperine  con- 
tent.    See  tables  on  page  1134. 

4)  For  a  description  of  percolators  adapted  to  the  use  of 
volatile  liquids,  as  specified  for  use  in  this  connection  by  the 
Pharmacopoeia,  see  Part  I  under  ''Apparatus  used." 

5)  With  respect  to  the  manner  of  exhausting  the  drug,  it  is 
thought  that  the  process  of  continuous  extraction  would  be  a 
distinct  improvement  over  the  present  pharmacopoeial  method. 
The  reasons  for  this  statement  have  already  been  given  in 
the  comments  of  the  preceding  oleoresins  and  need  not  be  re- 
peated here. 

6-7)  As  this  oleoresin  does  not  appear  to  undergo  any  notice- 
able changes  upon  exposure  to  the  air,  except  to  lose  a  small 
amount  of  volatile  oil,  the  conditions  under  which  the  solvent 
is  removed  from  the  percolate  are  not  as  important  as  in  the 
case  of  the  other  oleoresins.  The  time  necessary  to  complete 
the  preparation,  however,  can  be  considerably  shortened  if 
the  operation  is  completed  at  the  temperature  of  the  water 
bath,  for  which  reason,  this  procedure  is  thought  to  be  justi- 
fied. 

8)  The  Pharmacopoeia  directs  that  the  mixture  obtained  on 
evaporating  the  solvent  from  the  percolate  be  allowed  to  stand 
until  the  deposition  of  the  piperine  is  complete  and  that  the 
latter  then  be  separated  from  the  liquid  portion  by  straining 
through  purified  cotton.  The  object  to  be  attained  in  allow- 
ing the  piperine  to  deposit  is  not  understood  as  it  has  been 
found  in  actual  practice  that  the  liquid  portion. does  not  sep- 


21  g  DU  MEZ— THE  GALENICAL,  OLEORESINS 

arate  as  a  rule,  but  that  the  whole  sets  to  form  a  semi-solid 
mass  owing  to  the  large  amount  of  piperine  present.  The 
means  by  which  the  separation  of  the  piperine  was  accomp- 
lished in  the  laboratory  appears  to  be  more  rational  and  is  as 
follows:  the  mixture  was  heated  on  the  water  bath  until  the 
portion  constituting  the  oleoresin  was  quite  fluid  when  it  was 
filtered  through  cotton  with  the  aid  of  a  suction  pump.  The 
piperine  which  deposited  from  the  filtered  oleoresin  on  cool- 
ing was  finally  separated  by  decantation. 

9)  As  the  oleoresin  loses  volatile  oil  on  exposure  to  the  air,, 
it  should  be  kept  in  well-stoppered  bottles. 

Yield. 

The  yield  of  oleoresin  to  acetone  or  ether  is  about  4.5  to  6.5 
per  cent.  With  petroleum  ether,  a  yield  of  3.2  per  cent,  was  ob- 
tained in  the  laboratory.  Aside  from  the  effect  which  the  solvent 
has  upon  the  amount  of  the  oleoresin  obtained,  the  temperature  at 
which  the  piperin  is  separated  is  a  factor  to  be  considered.  The 
higher  the  temperature  at  which  this  is  accomplished,  the  greater 
the  amount  of  piperine  remaining  in  solution  and  the  greater 
the  yield  of  finished  product,  and  visa  versa. 

In  the  tables  which  follow,  the  yield  of  total  extract  is  fre- 
quently reported  as  oleoresin.  These  reports  should  not  be 
confused  with  those  pertaining  to  the  official  preparation,  which 
consists  of  the  liquid  portion  only,  the  precipitated  piperine 
and  other  insoluble  material  having  been  removed.  Data  of 
this  kind  have  been  included  here  for  the  sake  of  comparison 
with  results  of  a  like  nature  obtained  in  the  laboratory  and  in 
order  to  point  out  the  erroneousness  of  such  reports. 


OLEORESIN  OF  PEPPER 


217 


Table  123 — Yield  of  oleoresin  as  reported  in  the  literature. 


Observer 

Yield  of  oleoresin  to- 

Date 

Alco- 
hol 

Ace- 
tone 

Ether 

Other  solvents 

1888 

Trimble 

Per  ct. 

Per  ct. 

Perct. 

8.79 

Per  cent. 

J  Benzin 

1            2.80           J 

Represents      total 

1892 

Bei  iii^er 

9.97 
5.93 

yield  of  extract- 
tive  matter. 

Sherrard 



5.00  to 
6.70 

8.84 

9.64 

5.50 

8.70 

10  15 

10.04 
10.87 
12.88 

Yield  of  oleoresin. 

.....1 

Reported  as  yield 

Ballard 

...            .          f 

of"  oleoresin   (' ) 

1903 

Patch 

, . ) 

liidies.  Total  ex- 
tract. 
Pepper  from  Gua- 

deloupe. Total 
extiacL. 

1913 

coa.stof  Daliomey. 
Total  extract. 

Enifelhardt 

I 

Represents     total 

:::::::  ::::::::::i 

» Solvent   (?)...  . 

1             9.20            ] 
10.60            1 
11.00             f 
12.50           J 

yield  of  extract. 

,. 

Reported  as  yield 

(1)    Undoubtedly  represents  total  extract. 


Table  124 — Yield  of  oleoresin  as  obtained  in  the  laboratory. 


Observer 

Yield  of  oleore.sin  to— 

Date 

Alco- 
hol 

\ce- 
tone 

Ether 

Pptrol. 
ether. 

Remarks 

1916 

Du  Mez 

Per  ct. 
11.10 

5.32 

Per  ct. 
lO.fiS 

5.09 

Per  nt. 
10.42 

4.44 

Perct. 
7.14 

3.20 

Repre-ents.  total  ex- 
tract. 

Rei  resents  the  por- 
tion (iecaiitod  and 
waslied  from  the  de- 
posited piperine. 

21g  DU  MEZ— THE  GALENICAL.  OLEORESINS 

Chemistry  of  the  Drug  and  Oleoresin. 

Tabulation  of  Constituents. 

The  chemistry  of  black  pepper  has  been  the  subject  of  a 
number  of  investigations^  conducted  during  the  past  century. 
As  a  result  of  these  investigations,  the  presence  of  the  follow- 
ing substances  of  pharmaceutical  interest  has  been  established: 
volatile  oil,  piperine,  resin,  starch,  coloring  matter  and  inor- 
ganic constituents.  In  addition  to  the  foregoing,  the  presence 
of  fatty  oil,  piperidine  and  methyl  pyrroline  has  been  reported. 
The  following  are  stated  by  Kayser  and  others^  to  be  present 
in  the   oleoresin  when   prepared  with  ether: 


Eesin 

Volatile  Oil 

Coloring  Matter 

Fatty  Oil 

Ash 

Piperine 

Occurrence  of  Description  of  Individual  Constituents. 

Volatile  Oil:^  According  to  the  report  of  Schimmel  and 
Company,*  the  volatile  oil  of  pepper  is  a  colorless  or  yellowish- 
green  liquid,  having  a  phellandrene-like  odor.  At  15°C,  the 
specific  gravity  is  given  as  0.88  to  0.905  and  the  angle  of  ro- 
tation in  a  100  millimeter  tube  as  -5°  2'  to -[-2°  27'.  It  is 
stated  to  be  soluble  in  15  parts  of  alcohol  (90  per  cent). 

Early  attempts  to  determine  the  composition  of  the  oil  were 
made  by  Dumas,^  and  Soubeiran  and  Capitaine.®  In  1887, 
Eberhardt^  isolated  a  1-terpene  which  he  failed,  however,  to 


*  Among  those  who  have  reported  more  or  less  complete  analyses  of  pepper 
the  following  may  be  mentioned:  Pelletier,  Ann.  de  Chim.  et  de  Phys.  (1821), 
16,  p.  337;  Luca,  Tschenb.  f.  Scheidekiinstl.  u.  Apoth.  (1822),  43,  p.  81;  H. 
ROttger,  Arch.  f.  Hygiene  (1886),  4,  p.  183;  Richardson,  U.  S.  Dept.  of 
Agric.  Bull.  No.  13,  (1887),  p.  206;  Johnstone,  Chem.  News  (1888),  58,  p. 
235;  Kayser,  Chem.  Centralb.  (1888).  59,  p.261  ;  V^eigle,  Apoth.  Ztg.  (1893), 
8,  p.  468;  Hebebrand,  Zeitschr.  Unters.  Nahr.  u.  Genussm.  (1896),  p.  345; 
Winton,  Ogden  and  Mitchell,  Ann.  Rep.  Conn.  Exp.  Sta.  (1898),  p.  198; 
Balland,  Journ.  de  Pharm.  et  de  Chim.   (1903),  157,  p.  296. 

2  Kayser,  Weigle,  Balland,  I.  c. 

3  The  description  of  the  oil  as  here  given  is  for  that  obtained  from  the 
fruit  by  distillation  with  steam. 

*  Schimmel  &  Co.,  Semi-Ann.  Rep.,  Oct.  1893,  p.  34. 

»Ann.  d.  Chem.   (1835),  15,  p.  159;  Journ.  f.  prakt.  Chem.  (1835),  4,  p.  434. 
"Journ.  de  Pharm.  et  de  Chim.    (1840),  26,  p;  83. 
'Arch,  der  Pharm.   (1887),  225,  p.  515. 


OLEORESIN  OF  PEPPER  219^ 

identify.  Schimmel  and  Company*  have  reported  the  presence 
of  phellandrene  and  cadinene. 

From  0.70  to  2.2  per  cent,  of  volatile  oil  has  been  obtained 
from  the  fruits  by  steam  distillation.® 

Piperine}^  Piperine  (C17H19NO3)  was  first  isolated  by 
Oersted  in  1819.^^  It  is  a  weak  base  crystallizing  from  alcohol 
in  colorless,  shining,  four  sided  prisms,  the  melting  point  of 
which  is  128  to  129  °C.  It  is  slightly  soluble  in  boiling  water, 
readily  soluble  in  alcohol,  ether,  chloroform,  benzene  and  volatile 
oils,  slightly  soluble  in  petroleum  ether.  When  acted  upon  by 
solutions  of  the  alkalies,  it  is  hydrolyzed  breaking  down  into 
piperidine  and  piperic  acid.  Its  constitution  is  represented* 
by  the  following  structural  formula  :^^ 

H.      H, 


-O 


N  COCH:CH  CH:CH. 


^         C  H        H 

H,        H,  H        H 

The  quantity  of  piperine  present  in  the  fruit  of  black  pepper 
as  obtained  on  the  market  varies  to  a  considerable  extent.  This 
variation  is  very  probably  due  in  greater  part  to  natural  causes, 
such  as  the  age  of  the  fruit  before  harvesting,  climatic  condi- 
tions under  which  grown,  et  cetera}^  The  yield  is  variously 
stated  as  being  from  4.05  to  13.02  per  cent.^* 


*i.  c. 

»A  yield  of  0.7  to  1.69  per  cent,  of  volatile  oil  is  reported  by  C.  H.  Rich- 
ardson I.  c.  W.  Johnstone  obtained  0.98  to  1.87  per  cent.  Analyst  (1889), 
14,  p.  41.  G.  Teyxeira  and  B.  Ferrucio  give  the  yield  as  1.4  per  cent.  Bull. 
Chim.  Fharm.  (1900),  38.  p.  534;  Chem.  Centralb.  (1900),  71,  p.  736.  Schim- 
mel &  Co.   (1.  c.)  report  the  yield  as  1.3  to  2.2  per  cent. 

wRochleder,  Ann.  d.  Chem.  (1845),  54,  p.  255;  Babo  and  Keller,  Journ.  f. 
prakt.  Chem.  (1857),  72,  p.  53;  Rugheimer,  Ber.  d.  deutsch.  chem.  Ges. 
(1882),  15.  p.  1390. 

"Schweitz.  Med.  Journ.  (1819),  29,  p.  80;  Buchner,  Repert.  f.  die  Pharm.. 
(1820).  10,  p.  127. 

"Ladenburg-  and  Scholtz,  Ber.  d.  deutsch.   chem.   Ges.    (1894),  27,  p.   2958. 

"  Caseneuve  and  Caillot  report  the  piperine  content  to  be  as  follows : 
Sumatra.  8.10  per  cent;  Singapore,  9.15  per  cent;  Fenang,  5.24  per  cent.  Z.  c.. 
G.  Graff  gives  the  following  percentages  of  ether  soluble  nitrogenous  matter 
as  piperine:  Java,  5.85  to  9.5  per  cent.;  Lampong,  5.13  to  7.09  p^r  cent.; 
Penang,  9.12  to  9.42  per  cent;  Saigon,  6.16  per  cent.;  Singapore,  11.08  per 
cent.     Zeitschr.  f.  offentl.  Chem.  (1908),  14,  p.  425. 

"W.  Johnstone  obtained  5.21  to  13.03  per  cent  of  piperine  from  nine 
samples  of  black  pepper,  I.  c. 

C.  Heisch  gives  the  yield  as  4.05  to  9.38  per  cent.  Analyst  (1886),  11. 
p.  186. 

F.  Stevenson  reports  the  presence  of  7.14  per  cent,  or  piperine.  Ihid.  12^ 
p.  144. 


220  ^U  MEZ— THE  GALENICAL  OLEORESINS 

Resin.  The  presence  of  1.25  to  2.08  per  cent,  of  resin  in 
black  pepper  has  been  reported.^^  Buchheim/®  the  only  in- 
vestigator who  appears  to  have  attempted  to  isolate  the  same 
in  sufficient  purity  to  determine  its  composition,  states  that  it 
Is  a  condensation  product  of  piperidine  with  an  acid,  to  which 
lie  gives  the  name  Chavicinsaure.  He  assigns  the  name  Chavicin 
to  this  compound,  and  describes  it  as  a  yellowish-brown  mass 
■soluble  in  alcohol,  ether,  petroleum  ether  and  the  other  com- 
mon solvents. 

Coloring  Matter.  The  green  coloring  matter  in  pepper  is 
■stated  to  be  chlorophyll.^^  The  brown  coloring  matter  observed 
in  the  ethereal  or  alcoholic  extracts  has  not  been  identified. 

Fatty  Oil}^  The  presence  of  a  fatty  oil  in  black  pepper  must 
be  considered  doubtful  at  the  present  time.  Hirsch^^  states  that 
•a  microscopical  examination  of  the  fruit  revealed  the  presence 
of  a  fatty  oil  in  the  endosperm.  Kayser,^°  Weigle,^^  and  others 
mention  fatty  oil  as  one  of  the  constituents.  None  of  these 
investigators,  however,  appear  to  have  isolated  the  oil  in  a  pure 
state  or  to  have  described  it  in  detail.  Ditzler,^^  who  made  this 
matter  the  subject  of  a  special  investigation,  concluded  that 
glycerides  were  absent.  Likewise,  Gerock^^  could  obtain  no 
fat  from  white  pepper. 

Piperidine. "^^  Piperidine  has  been  named  as  a  constituent  of 
black  pepper  by  Johnstone,^^  who  found  the  average  content 
of  nine  samples  to  be  0.56  per  cent.  Kayser^®  disputes  the  find- 
ings of  Johnstone  and  states  that  the  base  obtained  by  distilla- 
tion is  ammonia. 


^' Teyxeira  and  Ferruoio  grive  the  resin  content  as  1.25  per  cent.,  F. 
Stevenson  as  1.44  per  cent.   I.   c. 

F.  Blyth  reports  the  presence  of  1.7  to  2.08  per  cent.  Foods.  Their  Com- 
position and  Analysis   (1903).  p.   496. 

"Buchner's  n.  Repert.  f.  Pharm.  (1876),  25  p.  335;  Pharm.  Journ.  1876, 
36.  p.  315. 

"Arthur  Meyer,  Das  Chlorophyllkorn,  Leipzig    (1883),   p.   2. 

"In  the  literature  on  food  chemistry,  the  non-volatile  ether  extract  is 
Aisuolly  spoken  of  as  fat  or  fatty  oil.     See  "Wanton,   Ogden  and  Mitchell,   1.  c. 

^®  Flueckiger,  Pharmako gnosis  des  Pflanzenreiches    (1891),  p.   914. 

^'  I.  c. 

217.  c. 

«Arch.  d.  Pharm.    (1886),   224,  p.  103. 

2J  Ihid. 

2*  As  piperidine  is  one  of  the  products  obtained  when  piperine  ia  hydrolysed, 
It  is  quite  probable  that  it  is  not  a  normal  constituent  of  the  fruit  but  is 
'formed  when  the  powdered  material  is  subjected  to  distillation. 

2*  I.    c. 

2«  I.    c. 


OLEORESIN  OF  PEPPER 


221 


Piperidine  is  a  colorless  limpid  liquid  having  a  specific 
gravity  of  0.8591  at  25  °C,  and  boiling  at  106.3 °C."  It  m 
stated  to  have  an  odor  resembling  both,  that  of  ammonia  and 
pepper.  It  is  a  powerful  base  behaving  generally  like  am- 
monia in  its  action  on  the  metallic  bases.  It  is  soluble  in  all 
proportions  in  alcohol  or  water.  It  has  the  following  struc- 
tural formula.^®. 


Methyl-Pyrroline.  Pictet  and  Court-*^  report  the  occurrence^ 
of  0.01  per  cent  of  methyl-pyrroline  in  black  pepper  obtained 
from  Singapore.  The  exact  constitution  has  not  been  deter- 
mined, but  the  authors  are  of  the  opinion  that  it  is  a  C-methyl 
pyrroline  represented  by  one  of  the  following  formulas: 


Ash.  The  basic  elements,  K,  Na,  Mg,  Ca,  Fe  and  Mn,  com- 
bined with  the  acids,  HCl,  H3PO4,  H2SO4,  HgSiOg  are  the  com- 
ponents of  the  ash  of  black  pepper  as  determined  by  Rottger**' 
and  others.^^ 

The  average  ash  content  of  black  pepper  is  stated  by  Blyth^^ 


2^Ferkin,  Chem.  Soc.  Journ.    (1889),  55,  p.  699. 

28Hofmann,  Ber.  der.  deutsch.  chem.  Ges.  (1879),  12,  p.  985;  Koenigs, 
Ibid.,  p.  2341;  Ladenburg,  Ibid.  (1885),  18,  pp.  2956  and  3100. 

*»  Pictet  states  that  he  was  able  to  isolate  pyrrolidine  and  N-methyl  pyrro- 
line from  various  leaves  by  steam  distillation  after  treatment  with  sodiuno 
carbonate.  He  is  of  the  opinion  that  the  methyl  pyrrolines  undergo  re- 
arrangement forming  pyridine  and  quinoline  rings,  thus  giving  rise  to  the- 
more  complex  alkaloids.  Arch.  Sci.  Phys.  Nat.  (1905),  19,  p.  329;  Ber.  d- 
deutsch.  chem.  Ges.   (1907),  40,  p.  3771. 

"Arch.  Hyg.    (1886),  4,  p.  183.     „ 

»Blyth,  Chem.  News  (1874),  30,  p.  170. 

«2  Ibid. 


,"222  DU  MEZ— THE  GALENICAL,  OLEORESINS 

to  be  4.845  per  cent.     As  high  as  8.99  per  cent,  has  been  re- 
ported.^^. 

Constituents  of  Therapeutic  Importance 

The  oleoresin  of  pepper  is  said  to  be  used  chiefly  in  the  South, 
where  it  is  administered  with  quinine  in  the  treatment  of  ''in- 
termittent fever."  Its  value  in  this  connection  is  accounted 
for  by  the  presence  of  piperine  which  has  been  shown  to  be  an 
:active  antiperiodic.^  Piperdine  and  methyl  pyrroline,  if  pres- 
ent, would  impart  similar  properties,^  while  the  composition  of 
the  contained  volatile  oil  w^ould  indicate  a  carminative  action. 

PJiysical  Properties 

Color:  The  color  of  the  oleoresin,  when  the  latter  was  spread 
out  in  a  thin  layer  on  a  white  porcelain  surface,  was  observed 
to  be  a  greenish-brown,  closely  resembling  that  of  the  oleoresin 
of  cubeb  when  prepared  from  the  ripe  fruits.  The  so-called  oil 
of  black  pepper,  sometimes  sold  as  a  substitute  for  the  official 
oleoresin,  is  stated  to  be  considerably  darker  in  color  due  to  the 
removal  of  the  greater  part  of  the  volatile  oil. 

Odor:  The  odor,  while  slight,  resembles  that  of  ground 
pepper. 

Taste:  The  taste  is  sharp  and  spicy,  the  sharpness  becom- 
ing more  noticeable  after  the  oleoresin  has  been  retained  in  the 
mouth  for  a  short  time. 

Consistence:  The  oleoresin  is  a  thick,  sticky  liquid  which 
•can  only  be  poured  with  difficulty.  The  fluidity  is  greatly  in- 
creased by  heating  the  preparation  on  a  water  bath. 

Solubility:  The  oleoresin  is  completely  soluble  in  alcohol, 
ether,  acetone,  chloroform,  carbon  disulphide  and  glacial  acetic 
acid.  It  is  only  partially  soluble  in  petroleum  ether  and  is 
insoluble  in  water. 

Specific  gravity:  The  specific  gravity  of  the  oleoresin  is 
fairly  constant,  only,  when  similar  conditions  with  respect  to 


"Heish  reports  the  ash  content  of  8  samples  of  black  pepper  to  be  from 
4.35  to  8.99  per  cent.  Analyst  (1886),  11,  p.  186.  Others  who  have  reported 
on  the  ash  content  of  pepper  are  Bergman,  Zeitschr.  f.  Analyt.  Chem.  (1882), 
^1,  p.  535,  and  von  Raumer,  Zeitschr.  angew.  Chem.  (1893),  p.  453. 

^Wood,  Therapeutics,  Principles  and  Practice,   (1908),  p.   482. 

^Tunnicllffe   and  Rosenheim,   Centralbl.   f.   Physiol.    (1902),   16,    p.   93. 


OLEORESIN  OF  PEPPER 


223 


temperature  have  been  observed  during  the  separation  of  the 
precipitated  piperine.  A  comparatively  slight  difference  in  tem- 
perature causes  a  considerable  variation  in  the  amount  of  the 
latter  constituent  retained  in  solution,  which  results  in  a  cor- 
responding variation  in  the  specific  gravity  of  the  finished  pro- 
duct. This  effect  is  further  ncviced  in  connection  with  the 
menstruum  employed  in  extracting  the  drug,  e.  g.  petroleum 
ether  which  is  a  poor  solvent  for  piperine  yields  an  oleoresin 
relatively  low  in  specific  gravity.  With  respect  to  the  com- 
mercial samples  examined,  a  low  specific  gravity  was,  in  one  in- 
stance, found  to  be  due  to  the  presence  of  unevaporated  solvent. 
The  tables  which  follow  show  the  specific  gravity  of  the  samples 
examined  in  the  laboratory. 

Table  125 — Specific  gravities  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Specific 
gravity 

1 

1916 

DuMez 

Alcohol 

At  25°  C 
1.069 

2 

1.083 

3 

•♦ 

Ether 

1.056 

4 

•• 

Petrol,  ether 

0  981 

Table   126 — Specific   gravities    of   commercial   oleoresins. 

Sample 
No. 

Date 

Observer 

Source 

Specific 
gravity 

1 

1916 

DuMez 

Squibb  &  Sons 

At  25°  C 
0.985' 

2 

Sharp  &  Dohme 

1.061 

The  odor  of  ether  was  very  noticeable. 


Refractive  index:  The  refractive  index  of  this  preparation 
as  observed  in  the  laboratory  was  not  constant,  varying  from 
1.521  to  1.696.  From  an  inspection  of  the  first  of  the  tables 
which  follow,  it  would  appear  that  this  variation  was  a  result 
of  the  influence  of  the  solvent  employed  in  extracting  the  drug. 
While  the  solvent  undoubtedly  exerts  an  influence  in  this  con- 
nection, it  does  so  indirectly,  that  is,  through  its  effect  on  the 
piperine  content.^     The  latter,  however,  is  also  influenced  by 


*  See  discussions   under   "Piperine   content"    and    "Yield   of   oleoresin, 
spectively. 


224 


DU  MEZ— THE  GALENICAL  OLEORESINS 


the  temperature  at  which  the  preparation  is  finished — the  tem- 
perature at  which  the  liquid  oily  portion,  which  constitutes  the 
official  oleoresin,  is  separated  from  the  deposited  material,  in- 
cluding the  excess  of  piperine.  In  the  case  of  commercial 
samples,  the  piperine  content  and,  therefore,  the  refractive  in- 
dex may  also  be  affected  by  the  presence  of  unevaporated 
solvent.  The  results  obtained  in  the  laboratory  in  the  deter- 
mination of  this  property  are  given  in  the  tables  which  follow. 

Table  127 — Refractive  indices  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Refractive 
index 

1 

1916 

DuMez 

Alcohol 

At  25°  C 
1  =559 

2  ..     . 

Acetone  . 

1  696 

3 

" 

Ether 

1  562 

4  

" 

Petrol,  ether 

1  521 

Table   128 — Refractive   indices   of  commercial  oleoresins. 


Sample 
No, 

Date 

Observer 

Source 

Refractive 
index 

1 

1916 

DuMez 

Squibb  &  Sons 

Sharp  &  Dohme 

At  25°  C 
1.501(a) 
1  560 

2     .     . 

(a)    Contained  ether. 


Chemical  Properties. 

Loss  in  iveiglit  071  Jieating:  A  loss  in  weight  varying  fromi 
9.49  to  11.52  per  cent,  was  obtained  for  the  laboratory  prepara- 
tions, when  heated  at  110° C,  showing  that  the  nature  of  the 
solvent  employed  in  extracting  the  drug  has  but  little  influence 
on  this  property.  With  respect  to  the  commercial  samples  ex- 
amined, the  loss  was  much  greater,  being  as  high  as  32.64  per 
cent,  in  one  case.  The  comparatively  great  loss  in  the  latter 
instance  was  due  to  the  presence  of  unevaporated  solvent 
(ether.)  The  results  obtained  in  the  determination  of  this 
constant  in  the  laboratory  follow. 


OLEORESIN  OF  PEPPER 


225 


Table  129 — Laboratory  preparations — loss  in  weight  on  heating. 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent,  of 
loss  on 
heatingr 

1 

1916 

DuMez ,.. 

Alcohol 

At  110°  C 
10.34 

2 

Acetone 

Ether 

Petrol,  ether 

11.52 

3 

'« 

10.91 

4 

ti 

9.49 

Table  130 — Commercial  oleoresins—loss  in  weight  on  heating-.. 


Sample 
No. 

Date 

Observer 

Source 

Per  cent,  of] 
loss  on 
heatin«r 

1 

1916 

DuMez 

At  llO^C 
17.52 

2 

Sauibb  &  Sons 

32.64» 

^  Unevaporated  solvent   (ether)   was  present. 

Ash  content:  The  ash  determinations  made  on  the  oleoresinsi 
prepared  in  the  laboratory  show  that  the  solvent  employed  ini 
their  preparation  is  the  chief  factor  influencing  the  results  ob- 
tained. The  official  product,  in  the  making  of  which  ether  was: 
the  solvent  used,  yielded  0.11  per  cent,  of  ash,  which  was  about, 
the  percentage  yield  obtained  for  one  of  the  commercial  samples; 
examined.  The  other  commercial  oleoresin  gave  0.29  per  cent, 
of  ash  indicating  the  use  of  acetone  in  its  preparation.  Both 
samples  contained  copper,  apparently,  however,  in  quantities 
too  small  to  noticeably  affect  the  weight  of  the  ash.  The  re- 
sults of  the  determinations  made  in  the  laboratory  follow:. 


Table  131 — Ash  contents  of  oleoresins  prepared  in  the  laJ>oratorvi 


Sample 
No. 

Date 

Observer 

Solvent 

Per  cent  of 

asli 

J 

1916 

DuMez 

Alcohol 

O.fS 
0.32 
O.ll 
0.05 

2 

Acetone 

8 

•' 

Ether ..'.'..'.'.*.* 

4 

•» 

Petrol,  ether 

226 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Table  132 — Ash  content  of  commercial  oleoresins. 


Sample 

No. 

Date 

Observer 

Source 

Per  eent.  of 

ash 

Foreign 
constituents 

1 

1916 

DuMez 

Squibb  &  Sons... 
Sharp  &  Dohme.. 

0.12  (a) 
0.29 

Copper 

2 

*  Contained  ether. 

Acid  number:  The  acid  number  of  the  oleoresin  when  pre- 
pared with  alcohol,  acetone  or  ether  was  found  to  be  about  19. 
In  the  case  of  the  two  commercial  samples  examined,  however, 
the  values  obtained  differed  to  a  considerable  extent,  being  19.2 
in  one  instance  and  27.5  in  the  other.  As  the  preparation 
represented  by  the  first  number  contained  considerable  unevap- 
orated  solvent,  this  difference  can  be  accounted  for  in  part.  The 
high  values  obtained  for  the  commercial  samples  are  thought  to 
be  due  to  their  relatively  low  piperine  content  or  to  a  partial 
decomposition  of  the  resin.  The  values  obtained  for  this  con- 
stant in  the  laboratory  follow. 


Table  133 — Acid  numbers  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Acid 
number 

J 

1916 

DuMez 

Alcohol   . . 

19.2 

2 

19.0 

3 

»• 

Ether   

18  9 

4 

•t 

Pfitrnl.-fithfir 

15.1 

Table   134 — Acid  numbers   of  commercial  oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Acid 
number 

1 

1916 

DuMez 

Sauibb  &  Sons 

19.2  (a) 

2 

Sharp  &  Dohme 

27  5 

(a)   Contained  ether. 


Saponification  value:  As  will  be  observed  in  an  inspection 
of  the  first  of  the  tables  which  follow,  the  saponification  value 
of  the  oleoresin  varies  with  the  solvent  employed  in  its  prepara- 
tion. This  appears  to  be  due  principally  to  the  effect  which 
the  nature  of  the  solvent  has  upon  the  piperine  content  of  the 


OLEORESIN  OF  PEPPER 


227 


finished  product,  e..  g.  the  piperine  content  of  the  preparation 
made  with  acetone  was  found  to  be  54.36  per  cent  and  the 
saponification  value  88.6,  while  the  oleoresin  when  prepared  with 
petroleum  ether,  contained  only  15.06  per  cent,  of  piperine  and 
gave  a  saponification  value  of  109.5.  Other  influences,  besides 
the  nature  of  the  solvent,  affecting  the  piperine  content  may 
likewise  produce  a  variation  in  the  saponification  value,  e.  g. 
the  temperature  at  which  the  preparation  is  made  and  the 
presence  of  unevaporated  solvent  in  the  finished  product.  The 
latter  may  also  have  a  direct  infiuence.  The  saponification 
values  as  found  for  the  oleoresins  examined  in  the  laboratory 
are  given  in  the  following  tables. 


Table  135 — Saponification  values  of  oleoresins  prepared  in  the 
laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

SaDonlflca- 
tion  value 

1 

1916 

DuMez 

Alcohol 

63  7 

2  

74  9 

3 

•« 

Ether  

83  5 

4     

•• 

Petrol,  ether 

86  8 

Table    136 — Saponification    values    of   commercial    oleoresins. 


Sample 
No. 

Date 

Observer 

Source 

Saponifica- 
tion value 

1 

1916 

DuMez 

Sharp  &  Dohme 

66.3 

2 

Saulbb  &  Sons 

73  7(a) 

(a)   Contained  ether. 


Iodine  value:  Iodine  values  ranging  from  88.6  to  95.4  were 
obtained  for  this  oleoresin  when  acetone,  alcohol  or  ether  were 
the  solvents  employed  in  its  preparation.  This  variation  is 
due  to  the  difference  in  the  piperine  content  of  these  oleo- 
resins as  a  result  of  operating  under  different  conditions  of 
temperature  when  preparing  the  same,  as  well  as  to  the  nature 
of  the  solvent.  In  addition  to  these  influences,  the  presence 
of  unevaporated  solvent  must  also  be  taken  into  consideration 
in  the  case  of  the  commercial  samples,  as  is  indicated  by  the 
values  given  in  the  following  tables. 


228  ^U  MEZ— THE  GALENICAL  OLEORESINS 

Table   137 — Iodine   values   of  oleoresins  prepared  in   the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Iodine  value 

1 

1916 

DuMez 

Alcohol 

Act'tone 

90.0 

2 

88.6 

3 

.»       *  ■ 

Eiher 

Petrol. -elher 

95.4 

4 

'• 

109.5 

Table  138 — Iodine  values  of  commercial  oleoresins. 


Sample 
No. 


Date 


1916 


Observer 


DuMez. 


Scource 


Sharp  &  Dohme. 
Stiuibb  &  Sons... 


Iodine  value 


83.7 
89.9  (a) 


(a)   Contained  ether. 


Special  Quantitative  Tests. 

At  the  present  time,  there  does  not  appear  to  be  a  method  in 
use  for  the  evaluation  of  this  oleoresin.  As  its  therapeutic 
properties  are  due,  in  greater  part  at  least,  to  its  piperine  con- 
tent,^ a  quantitative  method  for  the  estimation  ot  this  con- 
stituent appears  to  offer  the  best  means  of  determining  its 
quality. 

Method  for  the  Estimation  of  the  Pipeline  Content. 

In  the  laboratory,  the  amount  of  piperine  present  was  com- 
puted from  the  nitrogen  content  of  the  oleoresin,  the  latter 
being  determined  by  the  Gunning-Arnold^  method.  The  re- 
sults obtained  are  given  in  the  following  tables: 


Table  139 — Piperine  content  of  oleoresins  prepared  in  the  laboratory. 


Sample 
No. 

Date 

Observer 

Solvent 

Piperine 
content 

1  

1916 

DuMez 

Alcohol 

Per  cent. 
47.0 

2 

Acetone 

54.3 

8 

«» 

Ether 

51.3 

4 

•« 

Fetrol,  ether 

15  1 

1  See  under  "Constituents  of  therapeutic  importance.' 
'Bull.  No.  107.  Bur.  of  Chem.   (1912),  p.  162. 


BIBLIOGRAPHY 


229 


Table  140 — Piperine  content  of  commercial  samples. 


Sample 
No. 

Date 

Observer 

Source 

Piperine 
content 

1 

1916 

DuMez 

Sharp  &  Dohme 

Per  cent. 
27.3 

2 

Squibb  &  Sons 

33.8 

The  laboratory  samples  were  prepared  and  tested  during 
the  warm  months  of  summer,  which  accounts  for  the  high 
piperine  content.  A  very  considerable  amount  of  the  latter 
precipitated  out  during  the  colder  months  which  followed.  It 
is,  therefore,  thought  that  the  results  obtained  in  the  case  of 
the  commercial  products  are  the  more  typical. 

Adulterations. 

Copper  was  found  to  be  present  in  all  of  the  commercial 
samples  examined.     See  under  ''Ash  content.'* 

Bibliography. 
Planche  1823 

Von  den   pharmaceutischen   Zubereitungen   des  Lupulins. 

Mag.  f.  Pharm.,  1,  p.  183.     [Trommsdorff's  n.  Journ.  d. 
Pharm.,  7,  p.  345.] 

A  method  for  preparing  the  alcoholic  tincture  of  lupulin  is  given.  It  is 
further  stated  that  an  extract  similar  in  all  respects  to  the  resin  said  to 
have  been  isolated  by  Ives  results  when  the  alcohol  is  removed  from  the 
tincture   by  evaporation. 


Geiger,  Ph.  L.  1824 

Versuche  fiber  die  chemische  Zusammensetzung  der  Wurzel 

des  maennlichen  Parrenkrauts,  Polypodium  (Aspidium,  NepJi- 

r odium)  Filix  Mas. 

Mag.  f.  Pharm.,  7,  p.  38. 

The  article  is  a  review  of  Morin's  analysis  of  the  rhizome  of  male  fern 
with  a  note  pointing  out  that  Morin  was  not  the  first  investigator  to  make 
such  an  analysis,  but  that  Gebhardt  had  already  published  an  analysis  of 
the  same  in  1821  in  an  inaugural  dissertation  delivered  at  Kiel.  Gebhardt 
is  stated  to  have  used  ether  for  extracting  the  "oil." 


230  I^U  MEZ— THE  GALENICAL.  OLEORESINS 

Morin  1824 

Sur  la  composition  chimique  de  la  racine  de  fougere  male, 

Polypodium  filix  mas  Linn. 

Journ.  de  Pharm.  et  de  Chim.,  10,  p.  223.  [Mag.  f.  Pharm., 

7,  p.  38.] 

In  making  a  chemical  examination  of  the  male  fern  rhizomes,  the  author 
used  the  method  of  selective  solvents.  Upon  extracting  with  ether,  as  the 
first  solvent,  and  subsequently  evaporating  of  the  ether,  a  thick  green  fatty 
oil  was  obtained.  The  author  considers  this  fatty  substance  the  active 
principle. 

Meli  1825 

Nene  Erfahrungen  und  Beobachtungen  ueber  die  Art,  das 

Alkaloid  und  das  seharfe  Oel  des  Pfeffers  zu  gewinnen. 

Trommsdorff's  n.  J.  d.  Pharm.,  11,  p.  174.     [Bull,  de  scien. 

math.,  phys.  et  chim.,  1825,  p.  191.] 

It  is  stated  that  more  than  an  ounce  and  a  half  of  piperine  and  about 
four  ounces  of  a  sharp  tasting  oil  were  obtained  from  three  pounds  of 
black  pepper  by  extraction  with  alcohol. 

Peschier,  Ch.  1825 

Oel  des  maennlichen  Farrenkrauts  (Aspidium  Filix  Mas), 

ein  sehr  vorzuegliches  und  sicheres  Mittel  gegen  den  Bandwurm. 
Biblioth.  univers.,  Nov.  1825,  p.  205.     [Mag.  f.  Pharm.,  13, 

p.  188.] 

The  so  called  oil,  Euile  de  Fougere  Mdle,  is  directed  to  be  prepared  by 
extracting  the  powdered  male  fern  rhizomes  with  ether  and  subsequently  re- 
moving the  ether  by  warming  gently. 

Buchner,  A.  1826 

Extractum   Filicis  maris   resinosum. 

Repert  f.  d.  Pharm.,  23,  p.  433. 
The  preparation   of   this  extract   by  means   of   alcohol   instead  of  ether 
is  recommended.      The  product  thus  obtained  is  spoken  of  as  an  Extractum 
resinosum.       The  Kuile  de  Fougere  of  Peschier  is  spoken  of  as  the  harz- 
haltiges  Oel.     A  chemical  analysis  of  the  extrpiCt  is  also  given. 

von  Esenbeck,  Nees  1826 

Farrnkrautwurzelextrakt. 

Arch.  d.  Pharm.,  19,  p.  153. 
The  extract  is  reported  to  have  been  prepared  by  the  process  of  macera- 
tion, ether  being  the  solvent  employed.      Four  ounces  of  rhizomes  gathered 
in  August  gave  108  grains  of  extract. 


BIBLIOGRAPHY 


231 


1827 

Verhandlungen  des  pharmaceutischen  Vereins  in  Wuertem- 
berg.     Eepert.  f.  d.  Pharm.,  26,  p.  441. 

Zeller  is  stated  to  have  prepared  the  Extractum  radicis  Filicis  maris 
resinosum  according  to  the  method  suggested  by  Buchnerj  extraction  with 
alcohol.  The  extract  obtained  in  this  manner  from  rhizomes  gathered 
in  September  amounted  to  30  per  cent,  of  the  air  dried  drug. 

Batso,  Y.  1827 

Dissertatio  inaugur.  chemica  de  Aspidio  filice  mare 
Quam  cons,  et  auctor.  praes  et  direct,  etc.,  pro  summis  in  scient. 
et  arte  chemica  honor,  et  doct.  laurrite  cappess.  in  miivers. 
vindobon.  publ.  erudit,  disq.  snbmittit  Valentinus  Batso,  N.  H. 
Debreczino  Bibariensis  p.  37,  8.  Vindobonae,  typis  Antonii 
Pichler.  1826.  [Trommsdorff's  n.  Journ.  d.  Pharm.,  14,  2,  p. 
249.] 

In  addition  to  oil,  resin  and  fatty  wax,  the  author  finds  a  free  acid  and 
an  alkaloid  in  the  ethereal  extract  of  male  fern.  He  calls  the  acid  Acidum 
filiceum  and  the  alkaloid  Filicina.  He  attributes  the  activity  of  the  extract 
to  these  two  substances. 

Brandes,  R.  *  1827 

Ueber  das  Extractum  oleo-resinosum  Filicis. 
Arch  d.  Pharm.,  21,  p.  253. 

The  physical  properties  of  the  extracts  obtained  by  extracting  male 
fern  rhizome  with  ether  and  with  Liquor  anodynus,  respectively,  are  de- 
scribed. 

Buchner,  A.  1827 

Zur  medicinischen  und  chemischen  Geschichte  der  Filix  mas. 
Repert.  f.  d.  Pharm.,  27,  p.  337. 

The  author  speaks  of  the  ethereal  extract  of  male  fern  as  the  Extractum 
oleoso-resinosum  Filicis  maris.  It  is  stated  to  contain  a  volatile  oil,  a 
green  fatty  oil,  a  fatty  wax,  a  brown  resin  and  a  volatile  acid  (probably 
acetic  acid.) 

Van  Dyk  1827 

Ueber  das  Oleum  Filicis  maris. 
Arch.  d.  Pharm.,  22,  p.  141. 

Two  ounces  of  powdered  male  fern  rhizome  gave  70  grains  of  ethereal 
extract,  while  8  ounces  of  the  rhizome  yielded  3  ounces  of  extractive  matter 


232  DU  MEZ— THE  GALENICAL  OLEORESINS 

to  alcohol.  The  extract  prepared  with  ether  is  stated  to  be  dark  olive- 
;green  in  color  and  of  the  consistence  of  honey,  that  prepared  with  alcohol 
.•greenish-brown  in   color  and  much  thicker. 

Oeiger,  Ph.  L.  1827 

Analytische  Versuche  mit  der  Wurzel  des  maennlichen 
Parrenkrauts  und  Darstellung  des  Gels  (01.  Filicis  Maris) 
^us  derselben. 

Mag.  f.  Pharm.,  17,  p.  78. 
The  ethereal  extract  when  prepared  from  green  rhizome,  by  extraction 
with  ether  in  a  Bealsche  Presse  is  said  to  be  a  yellowish-green  oily  sub- 
stance. 

An  analysis  of  this  extract  showed  the  presence  of  30  per  cent,  of  resin- 
ous material  soluble  in  alcohol,  50  per  cent,  of  a  fixed  oil  and  a  considerable 
amount  of  volatile  substances. 

TiUoy  1827 

Bereitungsart  des  Oels  des  maennlichen  Farrenkrauts. 
Journ.  de  Chim.  med.,  3,  p.  154.     [Geiger's  Mag.  f.  Pharm., 

18,  p.  157.] 

The  so-called  oil  of  male  fern  is  directed  to  be  prepared  by  extracting 
the  rhizome  with  alcohol.  The  alcoholic  liquor  thus  obtained  is  treated 
with  lead  subacetate,  filtered,  and  the  solvent  removed  by  distillation. 
The  resulting  oil  is  further  purified  by  dissolving  in  ether  and  evaporating. 

Dublanc,  H.  1828 

Extrait  oleoresineux  de  Cubebe. 
Journ.  de  Pharm.  et  de  Chim.,  14,  p.  41. 

The  author's  method  for  preparing  the  oleoresinous  extract  consists 
in  distilling  off  the  volatile  oil  with  water,  exhausting  the  dried  marc  with 
alcohol,  evaporating  off  the  alcohol,  and  mixing  the  residue  so  obtained 
with  the  volatile  oil. 

Meylink  1828 

Ueber  das  Extractum  oleo  resinosum  Filicis. 
Arch.  d.  Pharm.,  25,  p.  243. 

Two  ounces  of  the  powdered  male  fern  rhizome  are  reported  to  have 
yielded  58  grains  of  a  dark  green,  oily  extract  to  ether. 

Oberdoerffer  1826 

Ueber  die  Darstellung  des  Cubeben  Extracts. 
Arch.  d.  Apoth.  Ver.,  24,  p.  178. 

In  the  method  of  preparation,  the  oil  is  first  obtained  by  steam  distilla- 
tion, the  marc  remaining  in  the  still,  after  drying,  is  then  extracted  with 


BIBLIOGRAPHY  233 

alcohol.  The  residue  remaining  after  removing  the  alcohol  by  evapora* 
tion  is  mixed  with  the  volatile  oil,  this  mixture  constituting  the  so-called 
extract. 

Peschier,  Ch.  1828 

Ueber   mehrere   schon   frueher   erschienene   Analysen  der 

Farrenkrautwurzel     (Aspidium  filix  mas  L.)   und  neber   die 

Gewinnnng  seines  harzigen  Oels. 

Trommsdorff's  n.  Journ.  d.  Pharm.,  17,  p.  5. 

The  vermifuge  properties  of  male  fern  are  said  to  be  due  to  its  ol6o- 
resine  (oelliars)  content.  This  the  author  prepares  by  extracting  the 
drug  with  ether  and  subsequently  evaporating  the  solvent,  (p.  8.)  It  is 
further  stated  that  this  oleosesine  remains  perfectly  homogenous  after 
months  if  prepared  from  freshly  gathered  rhizomes,  but  deposits  a  white 
granular  substance  when  old  rhizomes  are  used  (p.  9.) 

According  to  the  author's  analysis  the  oleoresine  consists  of  a  volatile 
aromatic  oil,  a  fatty  oil,  resin,  stearin,  green  and  red  coloring  materials, 
acetic  and  gallic  acids. 

Winkler,  F.  L.  1828 

Einige  Worte  ueber  die  Bereitung  des  01.  Filic.  Maris. 
Geiger's  Mag.  f.  Pharm.,  22,  p.  48. 

The  ''oil"  extracted  with  ether  is  said  to  be  a  mixture  of  oil,  resin 
and  oxidized  tannin.  Twelve  ounces  of  rhizomes  gathered  in  February 
yielded  15  drachms  of  extract.  Two  drachms  of  this  extract  yielded  43 
grains   of   fatty   oil. 

Allard  1829 

•    Note  sur  rhuile  de  fougere. 
Journ.  de  Pharm.  et  de  Chim.,  21,  p.  292. 

The  powdered  rhizome  of  the  male  fern  is  directed  to  be  extracted  with 
alcohol  and  the  alcoholic  extract  after  evaporating  off  the  solvent,  washed 
with  water.  The  extract  is  then  further  purified  by  solution  in  ether  and 
subsequent  evaporation. 

Carpenter,  G.  W.  1829 

Observations  and  Experiments  on  Peruvian  Bark. 
Silliman's  Am.  Journ.,  16,  p.  28.     [Buchner's  Repert  f.  d. 

Pharm.,  34,  p.  446.]     . 

In  the  discussion  of  the  therapeutic  uses  of  the  various  constituents  of 
Peruvian  bark,  it  is  stated  that  Dr.  Chapman  of  Philadelphia  prescribed 
piperin  and  oil  of  pepper  in  combination  with  quinine.  The  oil  of  pep- 
per is  said  to  be  the  more  active  therapeutically,  one  drop  of  oil  being 
equivalent  to  three  grains  of  piperin  (p.  39.) 


234f 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Haendess  1^29 

Ueber  01.  filicis  maris. 
Arch.  d.  Pharm.,  28,  p.  212. 

Four  ounces  of  powdered  male  fern  rhizomes  gave  170  grains  of  ethereal 
extract.  Upon  treating  this  ethereal  extract  with  alcohol,  20  grains  were 
dissolved  leaving  a  residue  of  150  grains.  The  extract  first  obtained  was 
of  a  brownish  color,  after  treating  with  alcohol  it  assumed  a  beautiful 
green   color. 

Voget  1829 

Notiz  ueber  01.  filicis  maris. 
Arch.  d.  Pharm.,  30,  p.  104. 

According  to  the  author's  method  of  preparing  the  Oleum  filicis  maris, 
the  powdered  male  fern  rhizome  is  first  extracted  with  water.  After  dry- 
ing the  drug  is  then  extracted  with  ether.  Twenty-eight  grains  of  a 
brownish-green  extract  were  obtained  from  9  drachms  of  the  marc. 

Schuppmann  1830 

Extractum  resinosum  Seminis  Cynae. 
Buchner's  Repert.  f.  d.  Pharm.,  35,  p.  430. 

The  extract  is  directed  to  be  prepared  by  macerating  4  ounces  of  the 
coarsly  powdered  seed  with  16  ounces  of  ether  for  3  or  4  days,  decanting 
the  liquid  portion  and  evaporating  to  remove  the  solvent. 

Beral  1834 

Du  principe  du  gingembre,  et  formules  de  plusieurs  com- 
poses pharmaceutiques  dont  il  est  la  base  medicamenteuse. 
Journ.  de  Chim.  med.,  Pharm.  et  Tox.,  10,  p.  289. 

The  product  obtained  by  extracting  ginger  with  ether  is  designated 
Fiperoide  du  Gingemhre.  It  is  directed  to  be  prepared  by  extracting  in  a 
percolator  4  ounces  of  ginger  with  6  ounces  of  ether,  the  rate  of  flow  being 
so  regulated  that  the  operation  will  consume  not  less  than  2  hours.  It  is 
stated  that  5  scruples  of  piperoide  were  obtained  in  this  manner,  and  that 
€  scruples  can  be  obtained  if  the  residual  ether  is  forced  out  by  subse- 
quent percolation  with  alcohol  (40°).  The  piperoide  is 'reported  to  be 
soluble  in  ether,  anhydrous  alcohol  and  oils. 

•  1838 


Extrait  Oleo-Resineaux  de  Cubebe, 

Journ.  de  Chim.  med.,  Pharm.  et  Tox.,  14,  p.  366. 

It  is  stated  that  Hausman  prepared  the  oleoresinous  extract  of  cubebs 
by  macerating  the  powdered  drug  with  ether    (625  grams  of  ether  to  250 
grams  of  drug),  then  decanting  and  evaporating  the  ethereal  solution  to 
remove  the  solvent. 


BIBLIOGRAPHY  235 

Hornung  1844 

Pharmaceutisch-Chemische  Mittheilungen. 
Arch.  d.  Pharm.,  89,  p.  34. 

Three  ounces  of  fresh,  powdered  rhizomes  of  male  fern,  treated  with 
3  ouncs  of  ether  in  a  Verdraengungsapparat,  are  reported  to  have  yielded 
2   drachms   of   extract. 

Luck,  E.  1845 

Ueber  einige  Bestandtheile  der  Eadicis  Filicis. 
Ann.  d.  Chem.,  54,  p.  119. 

Upon  standing,  the  ethereal  extract  deposits  a  granular  substance  which 
can  be  obtained  quite  pure  by  pouring  off  the  supernatant  oily  layer  and 
washing  the  deposit  rapidly  with  ether.  The  washed  precipitate,  dis- 
solved in  ether,  crystallizes,  upon  evaporation,  in  rhombic  leaflets,  m.  p. 
160°C,  insoluble  in  alcohol  or  water.  The  crystals  were  not  obtained  in  a 
suflScient  degree  of  purity  to  determine  their  chemical  constitution. 

Procter,  Wm.,  Jr.  1846 

On  the  Ethereal  Extract  of  Cubebs. 
Am.  Journ.  Pharm.,  18,  p.  167.     [Pharm.  Jonm.,  6,  p.  319.] 

At  Dr.  Goddard  's  request,  Procter  prepared  a  * '  true  oleoresin ' '  of  cubebs 
by  extracting  the  drug  with  ether.  This  method  is  regarded  by  him  as  a 
great  improvement   over   the   method   of   Soubeiran. 

Bell  1846 

Oleoresinous  Extract  of  Cubebs. 
Pharm.  Journ.,  6,  p.  319. 

The  report  includes  a  reprint  of  Procter's  paper  on  the  ethereal  ex- 
tract of  cubebs  and  remarks  by  Ure,  at  whose  request  the  preparation  was 
made  and  by  whom  it  is  stated  to  have  been  used  with  success.  A  yield  of 
15  to  20  per  cent,  of  oleoresin  was  obtained. 

Procter,  Wm.,  Jr.  1849 

Remarks  on  oleoresinous  ethereal  extracts,  their  preparation 

and  the  advantages  they  offer  to  the  medical  practitioner. 
Am.  Journ.  Pharm.,  21,  p.  114. 

A  method  for  the  preparation  of  the  following  ethereal  extracts  is  given: 
capsicum,  chenopodium,  semen  contra,  ginger,  cardamom  and  pellitory. 
(p.  116.)  Several  forms  of  apparatus,  including  a  tin  percolator,  Mohr's 
apparatus  for  extracting  with  ether  and  Gilbertson's  diplacement  appara- 
tus are  also  described  as  being  useful  in  this  connection. 


?36 


DU  MEZ — THE  GALENICAL  OLEORESINS 


Bock,  H.  1851 

Analyse  der  Wurzel  nnd  des  Wedels  von  Filix  mas. 
Arch.  d.  Pharm.,  115,  p.  257.     [Am.  Jonrn.  Pharm.,  24, 

p.  61.] 

The  powdered  rhizomes  were  extracted  with  ether,  specific  gravity  0.720. 
By  this  means,  2000  grains  of  the  powder  are  reported  to  have  yielded  257.4 
grains  of  an  oily  extract  which  was  found  to  be  composed  of  volatile  oil, 
tannic  acid,  resin,  fatty  oil  stearin  and  chlorophyll. 

The  author  recommends  preparing  the  oleoresin  from  fresh  rhizomes  as 
he  states  that  the  greater  part  of  the  volatile  oil  is  lost  upon  drying  and 
the  fatty   oil  tends  to  become  rancid. 

Lncke,  E.  1851 

Ueber    einige   Bestandtheile    der    Wurzel   von    Aspidium 

Filix  mas. 

Jahrb.  f.  prakt.  Pharm.,  22,  p.  130.    [Arch.  d.  Pharm.,  119, 

p.  178 ;  Journ.  de  Pharm.  et  de  Chim.,  54,  p.  476.] 

A  crystalline  substance  resembling  the  Filicin  obtained  by  Trommsdorff 
eight  years  previous  was  isolated  from  the  ethereal  extract.  The  author 
calls  it  Filixsaeure  and  assigns  it  the  formula  C20H15O9  It  is  further  stated 
that  extracts  prepared  with  ether  contain  no  tannic  acid  or  sugar,  but 
filix  acid,  pteritannic  acid  and  fatty  oil  are  present.  Upon  being  saponi- 
fied, the  oil  yielded  Filixolinsaeure  (C42H40O4  +  H  O)  and  Filosmylsaeure. 


Von  der  Marck,  W.  1852 

Ueber  Verfaelschnng  der  Radicis  Filicis  maris. 
Arch.  d.  Pharm.,  120,  p.  87. 

The  botanical  characteristics  of  other  than  the  official  species  are 
enumerated  and  the  manner  in  which  they  differ  from  those  of  male  fern 
pointed  out. 

With  respect  to  the  male  fern  rhizomes,  the  author  gives  the  following 
information:  rhizomes  gathered  in  September  are  the  most  active  as  they 
contain  the  greatest  amount  of  oil.  In  the  preparation  of  the  extract,  only 
that  portion  of  the  rhizome  having  borne  fronds  in  the  year  collected, 
should  be  taken.  The  following  results  were  obtained  using  different 
parts  of  the  rhizome: 

1.)  Extract  from  portion  of  rhizome  which  had  borne  fronds  the 
previous  year.     Yield  7.8%  of  a  brownish-green  extract. 

2.)  Extract  from  portion  bearing  fronds  during  year  collected.  Yield 
8.2%  of  a  beautiful  green  extract. 

3»)  Extract  from  portion  which  will  develop  fronds  the  coming  year. 
Yield,  8.5%  of  a  beautiful  green  extract. 


BIBLIOGRAPHY  237 

Schuck,  F.  1852 

Ueber  Cubebin 

Buchner's  n.  Repert.  f.  d.  Pharm.,  1,  p.  213.    [Jahresb.  d. 
Pharm.,  12,  p.  34.] 

Cubebin  is  stated  to  be  slowly  deposited  from  the  ethereal  extract  of 
cubeb  upon  standing.  The  extract  prepared  from  17  ounces  of  cubeb 
gave  15  grains  of  cubebin. 

Bakes,  W.  C.  1853 

Extract  of  Capsicum. 
Am.  Journ.  Pharm.,  25,  p.  513. 

The  extract  was  prepared  at  the  request  of  a  physician.  Dilute  alcohol 
was  employed  for  exhausting  the  drug.  Eight  ounces  of  Capsicum  yielded 
two  ounces  of  extract. 

It  is  stated  that  a  simple  ointment  which  acts  as  a  rubiafacient  in  20 
minutes  may  be  prepared  by  mixing  one  drachm  of  this  extract  with  1 
ounce  of   simple  cerate. 

Livermore  1853 

Extract  of  Lupulin. 

Am.  Journ.  Pharm.,  25,  p.  294. 
The  extract  is  directed  to  be  prepared  by  maceration,  using  alcohol  as 
the  solvent.       Sixty-six  per  cent,  of  extractive  matter  was  obtained  by  this 
treatment. 

Garot  and  Schaeuffele  1857 

Rapport  sur  le  produit  oleo-resineux  de  cubebe  obtenu  a 

Taide  du  sulfure  de  carbone. 

Journ.  de  Phai-m.  et  de  Chim.,  65,  p.  368. 

The  article  is  on  the  experimental  preparation  of  the  oleoresin  of  cubebs 
with  carbon  disulphide.  This  solvent  is  proven  to  be  worthless  for  this 
purpose  on  account  of  the  large  amount  necessary  for  extracting  the  drug 
and  on  account  of  the  difficulty  in  removing  it  by  evaporation. 

Landerer,  X. 

Ueber  Cubebinum. 

Arch.  d.  Pharm.,  139,  p.  302. 

The  so-called  cubebin  was  obtained  in  the  preparation  of  Extractum 
Cubebarum  oleoso-resinosum,  for  which  a  mixture  of  ether  and  alcohol  was 
used.  Upon  standing  in  a  cool  place,  needle-like  crystals  adhering  in 
groups  were  noticed.  These  crystals  were  soluble  in  warm  alcohol  and 
gave  a  carmine  red  color  with  sulphuric  acid. 


238 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Procter,  Wm.,  Jr.  1859 

Formulae  for  the  fluid  extracts  in  reference  to  their  more 

general  adoption  in  the  next  pharmacopoeia. 

Proc.  A.  Ph.  A.,  8,  p.  265.     [Am.  Journ.  Pharm.,  31,  p.  548.] 

It  is  suggested  that  the  preparations  made  by  extracting  drugs  with 
ether  be  designated  as  Oleoresinae  in  the  next  pharmacopoeia.  Methods  for 
preparing  the  following  oleoresins  are  described:  " Oleoresina  Cardamom^ 
Oleoresina  CaropJiylli,  Oleoresina  Cuhelae,  Oleoresina  Filicis  maris,  Oleo- 
resina  LupuUnae,  Oleoresina  Piperis  Nigri,  Oleoresina  Pyrethri,  Oleoresina 
Satinae,  Oleoresina  xanthoxyli  and  Oleoresina  Zingiieris.'* 

Girtle  1863 

Extractum  Cubebarum  oleoresinosum. 
Pharm.  Centralh.,  3,  p.  608.    [Canstatt's  Jahresber.,  23,  p. 

178.] 

The  preparation  is  an  aqueous-alcoholic-ethereal  extract  with  which  the 
volatile  oil,  previously  obtained  by  distillation,  has  been  incorporated.  It 
is  said  to  represent  the  therapeutic  properties  of  the  entire  drug.  It  is 
also  stated  that  this  preparation  is  not  identical  with  the  Extr.  Cub.  oleoso- 
resinosum  of  Landerer  (1857.) 

Parrish,  E.  1864 

On  Capsicum. 
Proc.  A.  Ph.  A.,  12,  p.  262.    [Jahresb.  1  Pharm.  1,  p.  68.] 

In  discussing  the  constituents  of  capsicum,  Parrish  refers  to  the 
ethereal  extract  as  the  oleoresin. 


Bernatzik,  W.  1865 

Chemische    Untersuchung  der    Cubeben    mit    besonderer 

Beruecksichtigung     der     Wirkungsweise     ihrer     wesentlichen 

Bestandtheile. 

Buchner's    Repert.    f.    d.    Pharm.,    14,    p.    97.     [Arch. 

Pharm.,  179,  p.  123.] 

The  article  is  a  comprehensive  discussion  of  the  constituents  of  cubebs 
and  their  physiological  and  therapeutic  action. 

Based  on  the  results  of  clinical  experiments,  it  was  concluded  that  the 
desired  therapeutic  principle  is  the  resinous  constituent  and  that  the 
volatile  oil,  cubeb  camphor  and  cubebin  are  practically  of  no  therapeutic 
value.  A  method  for  preparing  the  Extractum  Cubeharum  resinosum,  in 
^vhich  cubebs  freed  from  the  volatile  oil  are  extracted  with  alcohol,  is 
given   (p.  139.) 


BIBLIOGRAPHY  239 


1866 


Procter,  Wm.,  Jr. 

Note  on  Oleoresina  Cubebae. 

Am.  Journ.  Pharm.,  38,  p.  210.  [Pharm.  Journ.,  25,  p.  620.] 
The  author  reports  the  results  obtained  in  the  extraction  of  cubebs  with 
ether,  alcohol  and  benzine.  The  yield  of  oleoresin  obtained  was  as  fol- 
lows: ether,  21.9  per  cent.,  alcohol,  27  per  cent,  benzine,  16.5  per  cent, 
(p.  212).  The  use  of  benzine  in  the  preparation  of  this  oleoresin  is 
not  recommended  as  it  does  not  extract  the  cubebin  completely. 

Rittenhouse,  H.  N.  1866 

On  Substitutes  for  Ether  and  Alcohol  in  the  Preparation 

of  the  Official  Oleoresins. 

Proc.  A.  Ph.  A.,  14,  p.  208.     [Am.  Journ.  Pharm.,  38,  p.  24.] 

The  feasibility  of  displacing  the  ether  remaining  in  the  exhausted  drug 
with  benzine,  glycerine  or  water  is  discussed.  From  experiments  conducted 
along  this  line,  it  was  concluded  that  benzine  would  be  the  most  preferable 
for  this  purpose.  A  working  formula  in  which  benzine  is  used  to  this 
end  is  described.  Cubebs  and  ginger  were  the  drugs  employed  in  the 
experiments. 

Paul,  C.  1867 

Sur  I'extrait  oleoresineux  de  cubebe. 
Journ.  de  Pharm.,  et  de  Chim.,  84,  p.  197. 

The  extract  is  directed  to  be  prepared  by  treating  the  powdered  drug 
successively  with  water,  alcohol  and  ether.  The  extract  so  prepared  iSi 
said  to  contain  all  of  the  medicinal  principles  of  the  original  drug. 

Pile  •  1867 

On  the  preparation  of  Oleoresins  with  benzine. 
Proc.  A.  Ph.  A.,  15,  p.  94. 

One  pound  of  cubebs  percolated  with  2  pounds  of  light  benzine,  specific 
gravity  86°,  Beaume,  is  stated  to  have  yielded  a  trifle  over  5  per  cent,  of 
oleoresin  of  a  pale  ash  color. 

It  is  further  stated  that  neither  benzine  nor  ether  completely  exhaust 
ginger,  but  that  alcohol  is  a  much  better  solvent  for  this  purpose. 

Heydenreich,  F.  V.  1868 

On  Cubebin  and  the  Diuretic  Principle  of  Cubebs. 
Am.  Journ.  Pharm.,  40,  p.  42. 

Eighty  ounces  of  cubebs  yielded,  when  extracted  with  ether,  19  ounces 
of  oleoresin  or  nearly  24  per  cent. 

The  results  obtained  in  the  administration  of  cubebin,  the  volatile  oil 
and  the  soft  resin  are  given. 


240  ^^  MEZ— THE  GALENICAL  OLEORESINS 

Rump,  C.  '  1869 

Extractum  Lupulini  aethereum. 
Arch.  d.  Pharm.,  189,  p.  232.    [Jahresb.  d.  Pharm.,  4,  p.  39.] 

The  extract  of  lupulin  is  directed  to  be  prepared  hj  macerating  the 
fresh  drug  with  ether,  decanting  and  evaporating  the  ethereal  solution  to 
the  consistence  of  a  thin  syrup. 

Squibb,  E.  1869 

Keport  of  the  Committee  on  the  Pharmacopoeia. 
Proc.  A.  Ph.  A.,  17,  p.  298. 

The  process  of  repercolation  is  stated  to  be  well  adopted  to  the  prep- 
aration of  the  oleoresins  and  that  it  materially  lessens  their  cost. 

Lefort,  M.  J.  1870 

Memoire  sur  les  extraits  sulfocarboniques,  et  sur  leur  emploi 

dans  la  preparation  des  huiles  medicinales. 
Journ.  de  Pharm.,  90,  pp.  102-110. 

In  considering  the  methods  of  medicating  oils,  the  author  proposes  pre- 
paring the  extract  of  the  leaves  of  Conium  maculatum  by  exhausting  the 
drug  with  carbon  disulphide  and  subsequently  removing  the  solvent  by 
evaporation. 

Hager,  1871 

Zur  Bereitung  des  Extractum  Filicis  aethereum. 
Pharm.  Centralh.,  12,  p.  457.    [Am.  Journ.  Pharm.,  44,  p. 

104.] 

It  is  stated  that,  if  the  rhizomes  are  dried  over  burned  lime  previous 
to  extraction,  and  anhydrous  ether  (Sp.  gr.  below  0.723)  used  as  the  ex- 
tracting solvent,  the  oleoresin  does  not  deposit  on  standing  but  remains 
perfectly  clear. 

Maiseh,  J.  M.  1872 

On  the  use   of  Petroleum-Benzine  in  Making   Oleoresins. 
Am.  Journ.  Pharm.  44,  p.  208.    [Pharm.  Journ.,  31,  p.  968; 

Proc.  A.  Ph.  A.,  21,  p.  138;  Year-Book  of  Pharm.,  10,  p.  328.] 

Petroleum  benzine,  sp.  gr.  0.700,  is  stated  to  have  been  used  to  advantage 
in  the  preparation  of  the  oleoresins  of  capsicum,  cubeb  and  ginger,  but. 
the  author  regards  the  use  of  this  solvent  in  the  place  of  ether  as  inad- 
missable  until  it  has  been  proven  that  the  proximate  principles  not  ex- 
tracted by  th(B  benzine  are  medicinally  inert. 


BIBLIOGRAPHY  241 

Buchheim  1873 

Fructus  Capsici. 

Vierteljahresschr,  f.  prakt.  Pharm.,  22,  p.  507. 
[Proc.  A.  Ph.  A.,  22,  p.  106.] 

The  capsicin  sold  by  the  firm  of  E.  Merck  is  stated  to  be  the  ethereal 
extract  of  the  capsicum  fruit. 

Kemington,  J.  P.  1873 

On  the  Use   of  Petroleum   Benzin   for   Extracting   Oleo- 

resinous  Drugs. 

Proc.  A.  Ph.  A.,  21,  p.  592. 

It  is  stated  that  benzin  does  not  extract  all  of  the  diuretic  principles 
from  buchu  and  that  its  use  for  extracting  the  oleoresinous  drugs  is  limited 
on  account  of  its  inflammability  and  great  volatility. 

Patterson,  J.  1875 

Aspidium  marginale,  Wildenow. 
Am.  Journ.  Pharm.,  47,  p.  292. 

The  ethereal  extract  compared  very  favorably  in  appearance,  taste  and 
color  with  the  best  German  oleoresin  of  male  fern  which  could  be  obtained 
upon  the  market.  An  acid  resembling  the  filicic  acid  of  Luck  was  isolated 
therefrom. 

Kruse  1876 

Versuch  einer  vergleichenden  Analyse  der  in  den  Monaten 

April,  Juli  und  October  1874,  in  der  Umgegend  Wolmars  gesam- 

melten  Radicis  filics  maris. 

Arch.  d.  Pharm.,  209,  p.  24. 

The  results  obtained  in  the  analyses  of  rhizomes  gathered  during  the 
months  of  April,  July  and  October  are  tabulated.  The  rhizomes  gathered 
in  April  and  October  were  found  to  have  a  more  intensive  green  color  and 
stronger  odor  than  those  gathered  in  July.  The  rhizomes  gathered  in 
April  and  July  yielded  a  yellow  colored  extract  while  those  gathered  in 
October  gave  a  beautiful  green  colored  product. 

Griffin,  L.  F.  1877 

Preparations  of  Cubebs. 
Am.  Journ.  Pharm.,  49,  p.  552. 

The  author  found  that  cubebs  yielded  16.5  per  cent,  of  oil  and  resin  to 
gasoline,  while  the  wax  and  cubebin  were  not  extracted.  He,  therefore, 
concludes  that  gasoline  is  adapted  to  the  making  of  a  good  oleoresin  of 
cubebs. 


242  DU  MEZ— THE  GALENICAL  OLEORESINS 

Wolfe,  L.  1877 

On  the  use  of  Petroleum  Benzin  in  Pharmacy. 
Am.  Journ.  Pharm.,  49,  p.  1. 

It  is  stated  that  benzin  does  not  extract  any  of  the  pungent  resins  from 
ginger,  no  cubebic  acid  from  cubebs,  no  piperin  from  pepper,  and  no 
santonin  or  resin  from  wormseed. 

Cressler,  C.  H.  '  1878 

On  Aspidium  marginale,  Swartz. 
Am.  Journ.  Pharm.,  50,  p.  290. 

The  author  prepared  an  oleoresin  from  what  he  thought  was  male  fern, 
but  later  proved  to  be  Aspidium  marginale.  According  to  his  report,  it 
proved  effective  in  expelling  tapeworm. 

Rohn,  E.  1878 

Recovering   Ether   in   the    Preparation   of   the   Ethereal 

Extracts. 

Schweiz.  Worchenschr.  f .  Chem.  u.  Pharm.,  — ,  p.  —   [Year- 

Book  Pharm.,  16,  p.  250.] 

The  author  recommends  mixing  the  exhausted  drug  with  water  and 
then  heating  the  mixture  over  a  direct  flame  up  to  60°  C,  when  the  ether 
remaining  in  the  marc  distills  over.  In  this  manner  three  kilos  of  ether 
are  stated  to  have  been  recovered  from  eight  to  ten  kilos  of  male  fern  used 
in  the  preparation  of  the  extract. 

Kennedy,       .  1879 

Aspidium  marginale. 
Am.  Journ.  Pharm.,  51,  p.  382. 

Favorable  results  in  the  expulsion  of  taenia  by  the  administration  of 
oleoresin  of   Aspidium   marginale  a'*©  reported. 

Thresh  1879 

Proximate  Analysis  of  the  Rhizome   (Dried  and  Decorti- 
cated) of  Zingiber  Officinalis  and  Comparative  Examination  of 
Typical  Specimens  of  Commercial  Gingers. 
Pharm.  Journ.,  39,  pp.  171  and  191. 

The  yield  of  ether  extract  is  given  as  follows:  Jamaica  ginger,  3.29  per 
sent.,  Cochin,  4.965  per  cent.,  African,  8.065  per  cent.  It  is  further  stated 
that  twice  as  much  ether  is  required  to  exhaust  the  African  ginger  as  it 
is  necessary  in  the  case  of  the  other  sorts  (p.  191.) 


BIBLIOGRAPHY  24$ 

Bowman,  J.  '  1881 

Aspidium  rigidum. 
Am.  JoTirn.  Pharm.,  53,  p.  389.    [Pharm.  Journ.  12,  p.  263.] 

A  crystalline  substance  thought  to  be  identical  with  the  Filixsaeure  of 
Luck  was  obtained  from  the  ethereal  extract  of  Aspidium  rigidum. 

Seifert,  0.  *  1881 

Einiges  ueber  Bandwurmkuren. 

Wien.  Med.  Wochenschr.,  31,  p.  1364.    [Centralb.  f.  klin, 
Med.  3,  p.  1884.] 

The  author  contends  that  the  extract  should  be  prepared  from  the 
peeled  fresh  drug  gathered  in  May  or  October  as  drying  causes  the  loss  of 
a  greater  part  of  the  volatile  oil.  The  ether  should  not  be  evaporated 
until  just  before  the  extract  is  to  be  dispensed. 

Maisch,  J.  M.  1883 

Comparison  of  Galenical  Preparations  of  the  United  States 

and  German  Pharmacopoeias. 

Am.  Journ.  Pharm.,  55,  p.  398. 

In  the  preparation  of  oleoresin  of  cubebs,  the  German  Pharmacopceia 
directs  that  a  mixture  of  equal  parts  of  ether  and  alcohol  be  used  as  a 
menstruum^  while  the  Z7.  S.  Pharmacopoeia  directs  that  ether  alone  be  used. 
In  the  preparation  of  oleoresin  of  aspidium,  the  solvents  are  the  same 
(ether)  but  the  German  Pharmacopoeia  directs  that  the  oleoresin  be  pre- 
pared by  maceration  instead  of  percolation  as  in  the  Z7.  S.  Piiarma^opodia, 

Kramer  1884 

Extractum  filicis  maris. 
Pharm.  Centralh.,  25,  p.  578. 

The  fresh  rhizomes  gathered  in  May  or  October,  are  directed  to  be  ex- 
tracted with, ether  containing  a  little  alcohol.  The  tincture  thus  obtained 
is  to  be  preserved  in  a  cool  place  and  the  oleoresin  prepared  therefrom 
immediately  before  dispensing. 

Berenger-Feraud  1886 

Valeur  taenifuge  de  la  fougere  de  Normandy. 
Journ.  de  Pharm.  et  de  Chim.,  14,  p.  321.   [Arch.  d.  Pharm., 

224,  p.  134.] 

The  author  states  that  the  rhizomes  gathered  in  Normandy  have  scarcely 
any  action  while  those  gathered  in  the  Vosges  or  Jura  mountainB  are  very 
active  as  taeniafuges. 


^44  ^U  MEZ— THE  GALENICAL  OLEORESINS 

Jones,  E.  W.  1886 

Amount  of  Starch  in  Ginger. 
Chem.  &  Drugg.,  28,  p.  413.    [Arch.  d.  Pharm.,  224,  p.  769.] 

The  yield  of  ethereal  extract  is  given  as  3.58  per  cent.,  of  alcoholic  extract 
:-as  3.38  per  cent. 


1887 


Extractum  Cubebarum  aethereum. 

Gehe  &  Co.  Handels  -Ber.  Sept.,  1887,  p.  50. 

It  is  stated  that,  upon  long  standing,  the  extract  of  cubebs  deposits  a 
crystalline  substance.  The  firm,  therefore,  cannot  guarantee  that  the 
•extract  will  remain  clear. 

Kremel,  A.  1887 

Notizen  zur  Pruefung  der  Arzneimittel. 

Pharm.  Post,  20,  p.  521.    [Archiv.  d.  Pharm.,  225,  p.  880.J 

Methods   for    the   identification    and   evaluation    of    the   ethereal   extract 

of  cubebs  are  presented.       The  chemical  constants  of  both  the  alcoholic 

and    ethereal    extracts    are    tabulated    (p.    522.)     Analytical    data    on  the 

alcoholic  and  ethereal  extract  of  male  fern  are  also  given   (p.  523.) 

Lippincott,  C.  P.  1887 

What  Are  the  uses  of  Benzine  and  the  Lighter  Petroleum 
Products  in  Pharmacy? 

Proc.  Penn.  Pharm.  Assoc,  10,  p.  156. 
The  six   official  oleoresins  were   prepared  using   "benzole"  as  the  ex- 
iiausting  menstruum. 

Keefer,  C.  D.  1888 

Aspidium  marginale,  Willdenow. 
Am.  Journ.  Pharm.,  60,  p.  230. 

The  author  states  that  the  ethereal  extract  of  the  rhizomes  of  Aspidium 
marginale  contains  0.61  per  cent,  of  resin,  and  chlorophyll.  Filicic  acid 
could  not  be  identified. 

:Siggnis,  F.  M.  1888 

Comparative  value  of  commercial  gingers. 
Am.  Journ.  Pharm.,  60,  p.  278. 
The  following  percentages  of   resin  were  obtained  on  extracting  ginger 
<with  alcohol,  sp.  gr.  0.820. 

Jamaica,  unbleached    5.0     per  cent. 

Jamaica,  bleached    4.8 

East   Indian    6,65 

East  Indian  6.57 

African     6.17 

African     7.00 


BIBLIOGRAPHY  245» 

Trimble,  H.  1888 

The  Comparative  Extractive  Powers  of  Ether  and  Benzin. 
Proe.  Penn.  Pharm.  Assoc.,  11,  p.  60. 

The  following  percentages  of  oleoresin  were  obtained  on  extraction 
with  ether:  aspidiiim,  6,51  per  cent;  capsicum,  19.5  per  cent;  cubebs,. 
21.26  per  cent;  lupulin,  60.59  per  cent;  pepper,  7.89  per  cent,  and  ginger, 
3.07  per  cent.  The  same  drugs  yielded  to  benzin  5.9,  18.5,  16.65,  7.04,  2.8- 
and  2.48  per  cent.,  respectively. 

Greenwalt,  W.  G.  1889 

Oleoresin  of  Male  Fern. 
Am.  Journ.  Pharm.,  61,  p.  169.    [Proc.  A.  Ph.  A.,  37,  p.- 

379.] 

The  sediment  deposited  by  the  ethereal  oil  of  male  fern  was  found  by^ 
actual  test  to  be  as  active  as  the  supernatant  oil;  experiment  is  thus  said 
to  help  out  the  statement  (U.  S.  P.  1880)  that  the  granular  deposit  should' 
be  thoroughly  mixed  with  the  liquid  portion  before  being  used. 

Minner,  L.  A.  1890 

Oleum  Peponis. 
Am.  Jour.  Pharm.,  62,  p.  274.  [Proc.  A.  Ph.  A.,  38,  p.  323.] 

The  pumpkin  seeds  comminuted  with  pumice  stone  are  directed  to  be 
extracted  with  ether.  Such  a  preparation  is  stated  to  have  proved  to  be- 
an effective  taenifuge,  whereas  Oleum  Peponis  was  ineffective. 

Dieterich  1891 

Extracta. 
Helfenberger  Ann.,  1891,  p.  29. 

One  sample  of  extract  of  male  fern  examined  showed  a  **  moisture  con- 
tent" of  2.7  per  cent,  and  gave  0.40  per  cent,  of  ash. 

Kuersten,  R.  1891 

Ueber  Rhizoma  Pannae,  Aspidium  athamanticum  Kunze. 
Arch.  d.  Pharm.,  229,  p.  258. 

The  author  found  no  filix  acid  in  the  ethereal  extract,  but  a  substance 
Tannasaeure  having  the  formula  C11H14O4.  A  fatty  and  volatile  oil  were 
also  isolated.  The  extract  was  found  to  be  as  active  as  the  extract  of 
male  fern  in  the  expulsion  of  tape  worm. 


246  ^U  MEZ— THE  GALENICAL  OLEORESINS 

Poulsson,  E.  1891 

Ueber   den    giftigen    und    bandwurmtreibenden   Bestand- 

theil  des  aetherischen  Filixextractes. 

Arch.  f.  exper.  Path.  u.  Pharm.,  29,  p.  1. 

Filix  acid  is  stated  to  occur  in  two  forms,  amorphous  and  crystalline. 
"The  first  is  reported  to  be  therapeutically  active,  the  latter  is  not.  The 
-crystalline  acid  is  thought  to  be  an  anhydride  or  lactone  of  the  amorphous 
acid.      The  author  gives  the  name  Filicin  to  the  crystalline  acid. 

Rayman  1891 

Wirkung  des  Extr actum  Filicis  aether eum. 
Pharm.  Post,  24,  p.  933. 

It  is  stated  that  the  extract  of  male  fern  is  not  well  borne  when  taken 
internally  if  the  ether  has  not  been  completely  removed. 

Renter,  Ludwig  1891 

Ueber  die  Beziehungen  des  Filixsaeuregehaltes  zur  Wirk- 
ung des  Extractum  Filicis  aethereum. 

Pharm.  Ztg.,  36,  p.  245.     [Pharm.  Post,  24,  p.  511;  Am. 
Journ.  Pharm.,  63,  p.  288.] 

It  is  stated  that,  in  14  out  of  15  cases,  prompt  action  was  obtained  using 
an  extract  which  showed  no  deposit  of  filix  acid  and  which  left  no  residue 
of  filix  acid  after  treating  with  petroleum  ether.  On  the  other  hand 
tcxtracts  which  were  rich  in  a  deposit  of  filix  acid  also  showed  prompt  action. 

Professor  Robert  is  cited  as  stating  that  the  Russian  extract  is  about 
ten  times  as  active  as  the  German  extract  and  twenty  times  as  active 
as  the  French  extract. 

Riegel,  S.  J.  1891 

Ginger  and  its  Oleoresin. 

Am.  Journ.  Pharm.,  63,  p.  531.    [Year-Book  of  Pharm.,  29, 
p.  168.] 

Unbleached  Jamaica  ginger  and  East  Indian  ginger  (having  epidermis 
removed)  yielded  5  and  8  per  cent.,  respectively,  of  oleoresin  to  alcohol. 
"The  unbleached  Jamaica  ginger  gave  2.5  per  cent,  of  extractive  matter 
to  bens  in  and  the  East  Indian  ginger  gave  8  per  cent  of  oleoresin  to  ether. 
All  of  the  foregoing  oleoresins  were  found  to  be  completely  soluble  in 
alcohol  and  chloroform. 


1892 


Extractum  Alcannae  aethereum. 

Gehe  &  Co.,  Handels-Ber.  Apr.  1892,  p.  46. 

The  ether  extract  of  alkanet  root  is  stated  to  be  completely  soluble  in 
•oil  which  is  said  not  to  be  true  of  all  commercial  alkanet  extracts. 


BIBLIOGRAPHY  247 

Beringer,  G.  M.  1892 

Oleoresins. 

Am.  Journ.  Pharm.,  64,  p.  145.    [Proc.  A.  Ph.  A.,  40,  p. 
474;  Pharm.  Centralh.,  33,    p.    314;    Jahresb.    d.    Pharm.,    27, 

p.   589.] 

The  author  presents  experimental  data  to  show  that  acetone  might  be 
used  to  advantage  in  the  preparation  of  the  official  oleoresins.  He  es- 
pecially recommends  the  use  of  this  solvent  in  the  preparation  of  the 
oleoresin  of  ginger.  The  yield  of  oleoresin,  using  acetone  as  the  extract- 
ing solvent  for  the  various  drugs,  is  reported  to  be  as  follows:  aspidium, 
18  per  cent;  capsicum,  18  per  cent.  (25  per  cent,  when  the  drug  was  com- 
pletely exhausted);  cubebs,  21.75  to  25  per  cent;  lupulin,  71  per  cent; 
pepper,  5.93  per  cent;  ginger,  5.57  per  cent;  and  parsley  seed  24  per  cent. 

Dieterich  1892 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1892,  p.  44. 

Three  lots  of  extract  of  male  fern  gave  1.50,  2.10  and  1.50  per  cent., 
respectively,  of  * '  moisture ' '  and  showed  an  ash  content  of  0.55,  0.55  and 
0.55  per  cent.,  respectively. 

Kobert  "     1892 

Ueber  die  wirksamen  Bestandtheile    im    Ehizoma    Filicis 

maris. 

Pharm.  Post,  25,  p.  1325.    [Apoth. -Ztg.,  8,  p.  77;  Chem. 

Centralb.,  64,  p.  269 ;  Arch.  d.  Pharm.,  231 ;  p.  350,  Pharm.  Ztg., 

38,  p.  64.] 

The  author  states  that  the  volatile  oil  of  male  fern  is  therapeutically 
active  and  that  Poulsson  's  statement  based  on  the  work  of  Carlbohm, 
Liebig  and  Eulle,  that  the  activity  is  due  to  filix  acid  alone  is  erroneous. 
He  cites  as  an  example  the  activity  of  Aspidium  athamanticum  Kun^e,  which 
contains  no  traces  of  filix  acid  but  contains  the  volatile  oil. 

Sherrad,  C.  C.  1892 

Value  of  Oleoresinous  Drugs. 
Chem.  and  Drugg.,  40,  p.  523.    [Year-Book  Pharm.,  29,  p. 

157.] 

The  yield  of  oleoresin  obtained  using  ether  as  a  menstrum  is  reported 
to  be   as  follows: 

Capsicum,  4  samples,  15.5,  17.4,  18.3  and  18.4  per  cent;  cubebs,  9  samples, 
16.4,  18.8,  21.06,  21.9,  23,  24.7,  24.8,  and  24.8  per  cent;  ginger,  4  samples, 
3.85,  4.72,  5.2,  and  5.4  per  cent;  lupulin,  1  sample,  66.5  per  cent;  crude 
whole  male  fern  rhizomes,  2  samples,  9.27  and  9.87  per  cent;  peeled  male 
fern  rhizomes,  3   samples,   7.1,  7.26  and  8.9  per   cent. 


248  DU  MEZ— THE  GALENICAL.  OLEORESINS 

Weppen  and  Lueders  1892 

Ueber  Extractum  Filicis. 

Apoth.-Ztg.,  7,  p.  514.     [Pharm.  Ztg.,    38,    922;    Pharm. 
Post,  25,  p.  1173.] 

It  is  stated  that  the  extract  prepared  according  to  the  D.  A.  Ill  should 
have  a  yellowish-green  color  but  not  a  deep  green  color.  Preparations 
having  a  deep  green  color  probably  have  chlorophyll  or  copper  salts  added 
to  them.  Copper  can  best  be  detected  by  dissolving  the  ash  in  hydro- 
chloric acid  and  making  the  usual  tests  for  the  metal. 

Two  samples  (commercial)  of  a  deep  green  color  were  found  to  contaia 
0.056  and  0.044  per  cent,  of  copper,  respectively. 

1893 


Extractum  Filicis  aethereum. 

Gehe  &  Co.,  Handels-Ber.,  Apr.,  1893,  p.  43. 

The  condition  of  the  season  in  which  the  rhizomes  are  harvested  i» 
stated  to  have  a  marked  effect  on  the  color  of  the  extract.  Sometimes- 
the  genuine  extract  is  very  dark  green  in  color,  especially  in  dry  seasons. 

Beckurts  and  Peters.  1893 

Extractum  Filicis. 
Apoth.-Ztg.,  8,  p.  549. 

Upon  examination,  two  beautiful  green  samples  of  the  commercial  ex- 
tract were  found  to  contain  0.135  and  0.044  per  cent,  of  copper,  respectively^ 
evidently  added  for  the  purpose  of  coloring  the  product.  An  extract  pre- 
pared by  the  author  was  yellowish  green  in  color  and  contained  no  copper. 
A  warning  is  issued  against  the  use  of  copper  utensils  in  the  preparation 
of  the  extract. 

Dieterich  1893 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1893,  p.   38. 

One  sample  of  extract  of  cubeb  showed  a  '*  moisture '^  content  of  32.7" 
per  cent,  and  gave  0.50  per  cent  of  ash  (p.  39). 

Three  samples  of  extract  of  male  fern  contained  1.15,  1.60  and  1.75  per 
cent,  of  ''moisture"  and  gave  0.50,  0.50  and  0.50  per  cent,  of  ash,, 
respectively    (p.  39). 

Dyer  and  Gibbard  1893 

Determination   between    Genuine    and   Exhausted   Ginger. 
Analyst,  18,  p.  197.    [Proc.  A.  Ph.  A.,  42,  p.  936.] 

The  ether  extract  of  genuine  ginger  is  stated  to  be  3.0  to  5.2  per  cent. 
After  exhausting  with  ether,  alcohol  was  found  to  yield  0.8  to  1.5  per  cent, 
additional  extractive  matter. 


BIBLIOGRAPHY  249 

Bedall  1894 

Extractum  Cubebarum  Aethereum. 
Pharm.  Ztg.,  39,  p.  49. 

The   author  states  that  the  extracts  having   a  green  color   give   a  more 

intensive  reaction  for  cubebin  than  those  having  a  brownish  color.       This 

does  not   apply  when   the  green   color   is  due  to  the  presence  of  salts  of 
copper. 

Dieterich  1894 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1894,  p.  72. 

Three  samples  of  extract  of  male  fern  were  found  to  contain  3.65,  2.32 
and  1.90  per  cent.,  respectively,  of  "moisture.'^  The  same  samples  gave  0.55, 
0.42  and  0.50  per  cent.,  respectively,  of  ash. 

Emmanuel,  L.  1894 

Do  Drugs  Supplied  by  the  Jobber  Comply  with  Pharmaco- 

poeial  Requisition.     If  Not,  Who  is  Responsible,  The  Jobber  or 

the  Retailer? 

Am.  Journ.,  Pharm.  56,  p.  358. 

A  sample  of  powdered  cubebs  obtained  from  an  Eastern  firm  yielded  18 
per  cent,  of  a  brown  oleoresin.  This  was  reported  to  the  seller  who  re- 
plied: ''the  TJ.  S.  Pharmacopoeia  specifies  the  unripe  fruit,  but  this  is 
jparely  found  in  the  market,  the  regular  article  of  commerce  being  the  ripe 
fruit  which  contains  less  chlorophyll."  p.  360. 

Hell  &  Co. 

Zur  Kritik  liber  Extract-Vorschriften  und  ueber  fabrik- 
maessig  dargestellte  Extracte. 

Pharm.  Post,  27,  pp.  168-171.  [Journ.  de  Pharm.  et  de 
Chim.,  139,  p.  493.] 

Copper  is  stated  to  be  a  natural  constituent  of  the  male  fern  rhizome. 
Duplicate  analyses  of  a  sample  of  the  rhizomes  carefully  powdered  in  an 
iron  mortar,  and  incinerated  in  a  porcelain  dish  showed  0.0144  and  0.0148 
per  cent,  of  copper,  respectively.  An  ethereal  extract  prepared  in  the 
company's  laboratory  showed  0.0S3  per  cent,  of  the  metal  and  a  com- 
mercial sample  of  the  extract  gave  1.96  per  cent.  Likewise,  a  commer- 
cial sample  of  extract  of  cubeb  was  found  to  contain  0.40  per  cent,  of 
copper. 


250  DU  MEZ — THE  GALENICAL  OLEORESINS 

Poulsson,  E.  1894 

Beitraege  zur  Toxicologie  der  Farnkrauter. 
Pharm.  Post,  27,  p.  238. 

Two  new  acid  substances  C34HS8O14  and  C84H40O14  are  reported  to  have 
been  isolated  from  the  rhizomes  of  Polystichum  spinulosum.  They  were 
found  to  be  toxic. 


1895 


Extractum  Orleanae  aethereum. 

Gehe  &  Co.,  Handels-Ber.  Apr.,  1895,  p.  53. 


It  is  stated  that  good  * '  bixinreiche "  orlean  species  are  rare.      The  ex- 
tract is  said  to  be  used  for  coloring  "  Genussmitteln. ' ' 


1895 


Extractum  Cubebarum  aethereum  liquidium. 
Gehe  &  Co.,  Handels-Ber.,  Apr.,  1895,  p.  53. 

A  note  concerning  the  precipitation  of  resin. 


Bourquelot,  Em.  1895 

Keactions  d'identite  de  quelquess  medicaments  galenique» 

officinaux. 

Journ.  de  Pharm.  et  de  Chim.,  140,  p.  361. 

The  Extrait  de  Cubele  of  the  French  Codex  is  semi-liquid,  that  of  the 
German  and  Austrian  pharmacopoeias  of  the  consistence  of  fresh  honey* 
To  identify  the  oleoresin,  a  small  quantity  is  placed  in  a  white  porcelain 
dish  and  a  few  drops  of  concentrated  sulphuric  acid  are  added.  The  gen- 
uine oleoresin  gives  a  purple-red  color  immediately. 

Davis,  K.  G.  1895 

Ginger. 

Am.  Journ.  Pharm.  67,  p.  597.»  [Proc.  A.  Ph.  A.,  44,  p.  538.] 

The  yield  of  oleoresin  obtained  from  "ginger  by  the  official  process  wa» 
found  to  be  as  follows: 

Jamaica  ginger,  whole  rhizome,  bleached,  4.53  to  4.62  per  cent;  Jamaica 
ginger,  whole  rhizome,  unbleached,  2.82  to  4.41  per  cent;  Jamaica  ginger, 
powdered  unbleached,  4.48  per  cent;  Eaces  ginger,  powered,  bleached,. 
4.09  to  5.40  per  cent;  Eaces  ginger,  w^hole  rhizome,  bleached,  4.02  to  5.75 
per  cent;  African  ginger,  whole  rhizome,  5.75  per  cent;  African  ginger^ 
powdered,  6.27  per  cent. 


BIBLIOGRAPHY  251 

Dieterich  l^^^ 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1895,  p.  17. 

One  sample  of  extract  of  cubebs  contained  20.90  per  cent,  of  "mois- 
ture" and  showed  an  ash  content  of  0.47  per  cent.   (p.  17). 

A  sample  of  extract  of  male  fern  showed  a  "moisture"  content  of  1.75- 
per  cent,  and  gave  0.50  per  cent,  of  ash   (p.  18.) 

Hyers,  P.  1895 

Fluid  Extract  of  Cnbeb. 

Am.  Jonrn.  Pharm.,  67,  p.  519. 

The  following  percentages  of  oleoresin  are  reported  to  have  been  yielded 
by  cubebs  to  different  solvents:  ether,  22.45  per  cent;  alcohol,  14.48  per- 
cent; acetone,  18.48  per  cent;  petroleum  ether,  13.47  per  cent. 


1896 


Extractnm  Filicis  Ph.  G.  III. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1896,  p.  46. 

The  firm  attributes  the  uniform  activity  of  their  extract  of  male  fern  tO' 
the  fact  that  the  rhizomes  are  obtained  from  the  same  locality  each  year, 
that  they  are  collected  in  the  autumn  and,  after  carefully  garbling,  are 
immediately  made  into     extract. 

Fromme's  method  for  estimating  the  filix  acid  content  of  the  extract  is^ 
given. 

Alpers,  W.  C.  1896 

Oleoresin  Capsicum. 
Merck's  Eep.  5,  p.  593. 

The  author  states  that  he  obtained  a  yield  of  19  per  cent,  of  oleoresia 
after  removing  the  fat  by  Alteration  instead  of  5  per  cent,  as  usually  given 
in  the  text-books. 


Bocchi,  I.  1896 

Methoden  zur  Feststellung  der  Identitaet  und  der  Guete 

des  aetherischen  Filixextraktes. 

Boll.  Chim.  farm.,  1896,  p.  449.    [Apoth-Ztg.,  11,  pp.  597 

and  837;  Pharm.  Ztg.,  41,  p.  596.] 

Keactions  for  the  identification  of  filix  acid,  and  a  method  for  the  eval- 
uation of  the  extract  of  male  fern  are  given. 


252  ^^  MEZ— THE  GALENICAL  OLEORESINS 

Daccomo  and  Scoccianti  1896 

Die  Bestimmung  des  Gehaltes  an  Filixsaenre  im  kaeuflichen 

Extr actum  Filicis. 

Boll.  Chim.  farm.,  5,  p.  129.     [Pharm.,  Ztg.,  39,  p.  280; 

Jahresb.  d.  Pharm.,  31,  p.  583;  Apoth.-Ztg.,  11,  p.  174;  Proc. 

A.  Ph.  A..,  44,  p.  433.] 

The  filix  acid  content  of  a  number  of  samples  of  extract  of  male  fern 
(self  prepared  and  commercial)  was  found  to  vary  from  11.86  to  42.53 
per  cent.,  when  assayed  according  to  the  method  devised  by  the  authors. 
The  average  yield  of  extract  obtained  is  given  as  10  per  cent. 

The  quantity  and  quality  of  the  extract  is  stated  to  be  influenced  by 
the  locality  in  which  the  rhizomes  are  grown,  the  moisture  content  of  the 
drug  when  extracted,  and  the  solvent.  Ether,  specific  gravity,  0.720,  is 
stated  to  be  the  most  suitable  menstruum  for  this  purpose.  Ether,  specific 
gravity,  0.756,  yielded  17  per  cent,  of  a  brownish  colored  extract  of  a 
tarry  consistence.  The  presence  of  alcohol  is  said  to  retard  the  complete 
extraction  of  the  filix  acid. 

Dieterich  1896 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1896,  p.  33. 

One  sample  of  extract  of  male  fern  contained  1.62  per  cent,  of  "mois- 
ture" and  gave  0.45  per  cent,  of  ash. 

Kraft,  P.  1896 

Ueber     die     Wertbestimmung  von  Extractum  Filicis  und 

eine  neue  Bestimmungsmethode  der  Filixsaeure. 

Schweiz.    Wochenschr.    f.     Chem.    u.   Pharm.,   34,  p.  217. 

[Zeitschr,  d.  Allg.  Oesterr,  Apoth.  Ver.  34,  p.  798;  Zeitschr.  1 

Anal.  Chem.,  39,  p.  531.] 

It  is  stated  that  the  method  of  Daccomo  and  Scoccianti  for  the  evalua- 
tion of  the  extract  of  male  fern  does  not  give  the  filix  acid  content  but 
the  total  acid  content.  Extracts  examined  by  the  author's  method  gave 
from  0.4  to  10.0  per  cent,  of  filix  acid. 

A  new  constituent  which  the  author  calls  Filixwachs  was  isolated  from 
the  extract. 

Liverseege  1896 

The  Effect  of  Solvents  on  the    Analytical     Character    of 

Ginger. 

Pharm.  Journ.,  57,  p.  112.    [Apoth.-Ztg.,  11,  p.  639.] 
The   ethereal    extract    of  ginger   is   stated    to    amount   to    5.5    per   cent. 

The  yield  to  methyl  alcohol  is  given  as  6.5  per  cent. 


BIBLIOGRAPHY  253 

1897 

Extractum  Filicis,  Ph.  G.  III. 

Caesar  and  Loretz,  Geschaefts-Ber.,    Sept.     1897,    p.     62. 
[Pharm.  Centralh.,  38,  p.  34.] 

Investigations  carried  on  by  the  firm  showed  that  the  best  time  for 
harvesting  the  rhizomes  of  male  fern  is  from  the  middle  of  September 
to  the  end  of  October.  Ehizomes  collected  in  the  spring  yielded  an  ex- 
tract low  in  filix  acid  content. 

The  consistence  of  the  abstract  is  said  to  be  dependent  upon  variations 
in  the  rhizomes,  thus  rhizomes  rich  in  wax  give  an  extract  which  is  not 
fluid  at  ordinary  temperatures. 

Fromme  's  improved  method  for  estimating  the  filix  acid  is  given. 

1897 


Extractum  Filicis  aethereum,  P  G..  III. 
Gehe  &  Co.,  Handels-Ber.,  Apr.  1897,  p.  60. 

The  results  obtained  in  the  assay  of  male  fern  extracts  by  the  methods 
of  Daccomo  and  Scoccianti,  Bocchi,  and  Fromme  are  tabulated. 

Boehm,  R.    "  •  1897 

Beitraege  zur  Kenntniss  der  Filixsaeuregruppe. 
Archiv.  f.  exp.  Path.  u.  Pharm.,  38,  p.  35. 

In  addition  to  the  volatile  oil,  fixed  oil  and  filix  acid,  Boehm  isolated 
four  acid  substances  from  the  extract  of  male  fern,  viz:  aspidin  (C23H32OT), 
flavaspidic  acid  (CasHsgOg),  albaspidin  (CjzHjgO,)  and  aspidinol  (CijHuO*). 

Candussio  1897 

Ueber  die  Bereitung  des  Extractum  Filicis  aethereum. 
Pharm.  Post,  30,  p.  7. 
The  author  is  impressed  with  the  low  cost  of  the  commercial  extract  of 
male  fern  as  compared  with  the  cost  when  prepared  by  the  apothecary  him- 
self. The  examination  of  a  number  of  samples  from  the  best  German 
houses  showed  a  low  filix  acid  content  when  estimated  according  to  the 
method  of  Daccomo  and  Scoccianti.  They  were  all  of  a  beautiful  green 
color,  however. 

Dieterich  1897 

Extracta  spissa  et  sicca. 

Helfenberger  Ann.,  1897,  p.  244.    [Apoth.-Ztg.,  13,  p.  788; 
Pharm.  Centralh.,  39,  p.  775.] 

Two  samples  of  extract  of  male  fern,  D.  A.  Ill,  lost  4.5  and  4.72  per 
cent.,  respectively,  on  drying  at  100*0;  and  gave  0.43  and  0.52  per  cent, 
of  ash,  respectively. 

Dieterich  contends  that  a  standard,  which  does  not  take  into  consideratioB 


"254  ^U  MEZ— THE  GALENICAL  OLEORESINS 

the  volatile  oil  as  well  as  the  filix  acid,  is  worthless,  as  the  former  is  also 
active  as  a  taenifuge.  Old  extracts  which  are  inactive  show  the  normal 
Amount  of  filix  acid.  The  diminution  in  activity  is  said  to  be  due  to  the 
loss  of  the  volatile  oil  by  resinification  and  evaporation  (p.  248.) 

Dietericli  1897 

Extractum  Filicis  aetherum,  D.  A.  III. 
Extractum  Cubebarum  aethereum. 
Erstes  Dezennium  d.  Helfenberger  Ann.,  1886-1895,  p.  322. 

Eighteen  samples  of  extract  of  male  fern  examined  during  10  years 
showed  a  loss  upon  drying  at  lOO'C  of  from  0.60  to  9.73  per  cent.  The 
same  samples  showed  an  ash  content  varying  from  0.40  to  0.63  per  cent. 

Four  samples  of  ethereal  extract  of  cubeb  showed  a  loss  upon  drying 
at  100°C  of  20.13  to  32.7  per  cent.,  and  gave  0.10  to  0.52  per  cent,  of  ash. 

Glass  and  Thresh  1897 

Commercial  Gingers  and  Essence  of  Ginger. 
Pharm.  Journ.,  58,  p.  245.   [Am.  Journ.  Pharm.,  69,  p.  320.] 

Jamaica  ginger  was  found  to  yield  6.0  per  cent  of  extractive  matter 
to  ether;  Cochin,  4.33  per  cent;  African,  6.33  per  cent. 

Iiauren,  W.  1897 

Extractum  Filicis  spinulosae. 

Finska  Laekaresaellsk.  Handl.,  1897,  p.  9.    [Pharm.  Cen- 
tralh.,  39,  p.  975.] 

The  ethereal  extract  prepared  from  the  rhizomes  of  Aspidmm  spinulosum 
is  stated  to  be  as  active  a  taeniafuge  as  that  prepared  from  Aspidium  filix 
mas. 


Madsen,  H.  P.      .  1897 

Meddelelser  fra  Vesterbro  Apotheke  Laboratorium. 
Arch.  f.  Pharm.  og  Chem.,  54,  p.  269.    [Jahresb.  d.  Pharm., 

32,  p.  591;  Apoth.-Ztg.,  12,  p.  461.] 

Extracts  of  male  fern  from  Denmark,  Germany,  Bohemia,  central  Eus- 
sia  and  Livonia  were  tested  quantitatively  for  filix  acid  according  to 
Fromme's  method.  Those  from  Bohemia  and  central  Russia  gave  from 
0.71  to  0.97  per  cent,  of  filix  acid;  two  samples  from  Germany  gave  5.58 
and  9.58  per  cent.,  respectively;  an  extract  from  Wolmar  in  Livonia  gave 
13.07  per  cent;  the  extracts  from  Denmark,  with  two  exceptions  (6.07  and 
8.25  per  cent.),  gave  below  2  per  cent.    (p.  277.) 


BIBLIOGRAPHY  255 
1898 

Extr actum  Filicis  aetherum. 

Gehe  &  Co.,  Handels-Ber.,  1898,  p.  68.     [Pharm.  Centralh., 
39,  p.  298.] 

In  the  analyses  of  11  extracts  obtained  during  different  years,  6  were 
found  to  contain  aspidin,  0.2  to  3.0  per  cent.,  but  no  filix  acid;  4  samples 
contained  filix  acid  but  no  aspidin;  1  sample  showed  a  trace  of  aspidin 
and  a  small  quantity  of  filix  acid. 


1898 


Zur  Arzneiform  lind  Werthbestimmung  des  Filixextracts. 
Pharm.  Centralh.,  39,  p.  873. 

The   dilution  of  the  extract  of  male  fern  with  castor   oil  to  a  definite 
filix  acid  content  is  discussed. 


1898 


Extractum  Filicis,  Ph.  G.  III. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1898,  p.  72. 

A  continuation  of  the  firm's  investigations  concerning  the  influence  of 
time  of  harvesting  upon  the  quality  of  the  male  fern  rhizomes  has  shown 
that  they  do  not  contain  the  maximum  amount  of  active  constituents  until 
the  month  of  August.  They,  therefore,  conclude  that  the  rhizomes  should 
only  be  harvested  in  the  months  of  August,  September  and  October. 

It  is  further  reported  that  analyses  of  the  extracts  recently  prepared 
show  that  the  present  year's  (1898)  crop  of  rhizomes  is,  on  the  whole,  lower 
in  crude  filicin  content  than  that  of  the  preceding  year  (1897.) 

Bellingrodt,  Fr.  1898 

Ueber  Rhizoma  und  Extractum  Filicis. 
Apoth.-Ztg.,  13,  p.  869. 

The  crude,  and  purified  filicin  content  of  8  different  extracts  of  male 
fern  prepared  by  the  author  from  rhizomes  obtained  from  different  sources 
are  given.  Similar  data  in  the  examination  of  9  commercial  extracts  are 
also  reported. 

Dieterich,  K.  1898 

Zur  Wertbestimmung  und  Arzneiform  des  Filixextraktes. 
Apoth.-Ztg.,  13,  p.  788. 

The  addition  of  castor  oil  to  the  extract  of  male  fern  in  sufficient  quantity 
to  bring  the  filix  acid  content  to  a  definite  standard  is  recommended. 


256  I^U  MEZ— THE  GALENICAL,  OLEORESINS 

Duesterbehn,  F.  1898 

Rhizoma  und  Extractum  Filicis  in  therapeutiwher,  chem- 

ischer  und  toxicologischer  Beziehung. 

Apoth.-Ztg.,  13,  pp.  713,  720,  729  and  734. 

The  article  is  principally  a  review  of  the  literature  on  the  extract  of 
male  fern  and  its  constituents. 

Lefils  1898 

Zur  Herstellung  von  Filixextract. 

Pharm.   Centralh.,  39,  p.  901.     [Zeitschr.  d.  oest.  Apotk 
Ver.,  37,  p.  167;  Pharm.  Ztg.,  43,  p.  939.] 

The  author  advises  the  mixing  of  the  powdered  rhizomes  with  castor  oil 
before  preparing  the  extract  as  he  is  of  the  opinion  that  this  procedure 
will  retard  the  evaporation  of  the  volatil  oil  and  the  precipitation  of  the 
crystalline  filix  acid. 

Idris,  T.  H.  1898 

Notes  on  Extract  of  Ginger. 
Am.  Journ.  Pharm.,  70,  p.  466. 

The  alcoholic  extract  of  ginger  known  as  gingerine  does  not  contain  all 
of  the  aromatic  principles  of  the  rhizome,  as  most  of  the  essential  oil  is 
lost  on  removing  the  alcohol  upon  evaporation.  Acetone  boiling  at  SS^C 
was  found  to  be  the  most  suitable  solvent  for  extracting  ginger.  The 
acetone  extract  is  a  dark  brown  substance  of  treacly  consistence,  intensely 
pungent  and  at  the  same  time  possessing  the  full  aroma  of  ginger,  the 
quality  of  which  largely  depends  on  the  variety  of  ginger  used. 

Miehle,  Feodor  1898 

Eine  empf  ehlenswerte  Form  der  Verordung  von  Extractum 

Filicis. 

Apoth.-Ztg.,  13,  777.    [Pharm.  Centralh.,  39,  p.  873,] 

The  author  recommends  diluting  the  extract  with  castor  oil  in  order  to 
make  a  standard  preparation  containing  a  definite  amount  of  filix  acid. 
He  advises  the  introduction  of  such  a  preparation  into  the  D.  A.  lY, 
under  the  name  Extractum  Filicis  oleatum. 

Plzak,  F.  1898 

Extractum  Filicis. 
Pharm.  Centralh.,  39,  p.  687.      [Jahresb.    d.    Pharm.,  33, 

p.  547.] 

The  author  found  6.48  per  cent  of  filix  acid  in  the  extract  of  male  fern 
by  the  Kraft  method,  6.0  per  cent,  by  Fromme  's  old  method  and  5.2  per  cent* 
by  Fromme 's  improved  method. 


PIPLIOGRAPHY  257 

Wintan,  Ogden  and  Mitchell  1898 

Capsicum. 

Rep.  of  Conn.  Agr.  Exp.  Sta.  (1898),  p.  200. 
The   amount    of   extractive  matter    obtained   with   ether   from    different 
samples   of  red  peppers  is   given  as   follows:      Chilli   Colorado,   15.81   per 
cent;   peppers  from  Natal,   16.85  per  cent;   from  Nepaul,   21.31  per  cent; 
and  from  Zanzibar,   16.19  per  cent. 

• 1899 


Recently  Introduced  Remedies. 

Am.  Drugg.  &  Pharm.  Rec,  34,  p.  129. 
It  is  stated  that  the  extract  of  Filix  Spinulosa  is  an  ethereal  extract  of 
the  rhizome  of  Aspidium  spinulosum  and  that  it  has  been  recommended  as 
a  substitute  for  the  preparation  made  from  Aspidium  Filix-mas. 

1899 


Extractum  Filicis,  Ph.  G.  III. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1899,  p.  73. 
A  table  showing  the  crude  filicin  and  filix  acid  content  of  extracts  pre- 
pared from  15  of  the  better  samples  of  male  fern  rhizomes  obtained  from 
different  sources  in  Germany  is  given. 

Eesults  showing  the  difference  in  extractive  power  of  ether,  ap.  gr.  0.720 
and  ether,  sp.  gr.  0.728  are  also  given, 

Hausmann,  A.  1899 

Ueber  Extractum  Filicis  aethereum. 
Arch.  d.  Pharm.,  237,  p.  544. 

The  examination  of  21  commercial  extracts  of  male  fern  obtained  from 
various  sources  showed  that  aspidin  was  a  constituent  of  4  of  them.  As 
aspidin  is  said  to  be  found  only  in  Aspidium  spinulosum,  the  author  infers 
that  the  rhizomes  of  this  species  have  been  used  to  adulterate  the  official 
drug. 

A  method  for  the  detection  of  aspidin  is  given. 

1900 


Extractum  Filicis. 

Caesar  and  Loretz,  -Geschaefts-Ber.,  Sept.  1900,  p.  77. 

A  table  showing  the  crude  and  purified  filicin  content  of  12  samples 
of  extract   of  male  fern  is  given 

Attention  is  also  called  to  the  greater  tendency  of  the  extract,  prepared 
with  ether,  specific  gravity  0.728,  to  deposit  than  that  prepared  with 
ether,  specific  gravity  0.720.  The  deposited  material  is  reported  to  have 
been  identified  by  Boehm  as  filix  acid  and  a  wax-like  substance. 


258  ^^  MEZ— THE  GALENICAL  OLEORESINS 

1900 

Extractum  Filicis  aethereum. 

Gehe  &  Co.,  Handels-Ber.,  Apr.  1900,  p.  63. 

The  constituents  of  the  extracts  of  Aspidium  filix  mas,  A.  filix  femina 
and  A.  spinulosum  are  discussed. 

Maish,  H.  C.  C.  1900 

Oleoresins.    Economical  preparation. 

P.  C.  P.,  Alumni  Report,  March,  1900,  p.  49.    [Proc.  A.  Ph. 

A.,  48,  p.  495.] 
Maish    advises    the  use   of   the    Soxhlet    extraction   apparatus   for   pre- 
paring the  oleoresins  on  a  small  scale. 

Patch,  E.  L.  1900 

Answere  to  queries  issued  by  the  Scientific  Section  of  the 
American  Pharmaceutical  Association. 
Proc.  A.  Ph.  A.,  48,  p.  199. 
The  commercial  oleoresins  frequently  show  the  presence  of  acetone,  p.  205. 


1901 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1901,  p.  68. 
The  crude  and  purified  filicin  contents  of  8  batches  of  extract  of  male  fern 
prepared  during  the  year  are  presented  in  tabular  form. 

Bennet  1901 

Report  on  Commercial  Ginger. 
Pharm.  Journ.,  66,  p.  522. 
The  yield  of  extractive  matter  obtained  on  exhausting  ginger  with  ether 
and  alcohol  is  given  as  follows: 

Per  cent,  of  ether  extract: 

Jamaica  ginger    (whole),     2.57  to  6.41. 

*'  '*       (ground),  2.97  to  4.6. 

Per  cent,  of  alcoholic  extract  after  ether: 
Jamaica    ginger  (whole),     3.09  to  5.16. 
"  **        (ground),  3.01  to  4.16. 

Per  cent,  of  alcoholic  extract. 
Jamaica  ginger    (whole),     3.94  to  5.61. 

*'  '*        (ground),  3.41  to  5.67.  ^ 

Cochin  **        (whole),    4.91  to  6.74.  "  ' 

*'  **       (ground),  5.41  to  6.51. 

African        **        (whole),     5.41  to  6.61. 

"  *'        (ground),  5.14  to  6.47.  ^ 


BIBLIOGRAPHY  259 

Dieterich  1901 

Extracta  spissa  et  sicca. 

Helfenberger  Ann.,  1901,  p.  170. 
One  sample  of  extract  of  male  fern,  D.  A.  IV,  gave  5.23  per  cent,  of 
*' moisture"   and  0.32  per  cent,   of   ash    (p.   171). 

Matzdorfe,  M.  1901 

Wertbestimmnng  des  Khizoma  Filicis. 
Apoth.-Ztg.,  16,  pp.  233,  256  and  273. 
The  various  constituents  of  the  extract  of  male  fern  are  discussed  with 
respect  to  their  therapeutic  activity.  Of  these  filix  acid  is  thought  to 
be  the  most  important.  Tables  showing  the  crude  filicin  and  filix  acid 
content  of  ethereal  fluid  extracts  prepared  by  ordinary  percolation  and 
by  extraction  with  a  Soxhlet's  apparatus  are  given. 

Stoeder  1901 

Bestimmung  der  Filixsaenre  in  Extr actum  Filicis. 
Pharm.  Ztg.,   46,  p.  541. 
A  method  very  similar  in  all  respects  to  that  of  Fromme  for  the  esti- 
mation of  the  filix  acid  in  the  extract  of  male  fern  is  described. 


1902 


Oleoresin  of  Insect  Powder.  i,^ 

Southall  Bros.  &  Barclay,  Lab.,  Bep.,  10,  p.  20. 

This  oleoresin  is  said  to  be  extracted  from  the  powdered  drug  and  is 
offered  for  sale,  in  the  crude  form,  as  an  extract,  or  precipitated,  in  the 
form  of  a  coarse  powder. 

It  is  said  to  be  useful  as  a  basis  for  nursery  hair  lotions,  dusting  pow- 
ders and  similar  articles. 


1902 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1902,  p.  73. 
It  is  stated  that  the  crude  filicin  contains  the  amorphous  acid  recently 
shown  by  Kraft  to  be  the  active    principle    of    male    fern    extract.     The 
estimation  of  the  crude  filicin  will,  therefore,  be  continued  by  the  firm. 

Buttin,  L.  1902 

Extract  de  Fougere  male. 

Schweiz.  Wochenschr.  f.  Chem.  u.  Pharm.,  40,  p.  234. 
A  short  review  of  the  early  work  on  the  constituents  of  the  extract  of 
male  fern  is  given. 
The  variation  in  the  constituents  of  the  rhizomes  dne  to  the  locality  in 


2^0  ^^  MEZ— THE  GALENICAL  OLEORESINS 

which  they  are  grown,  the  time  of  the  year  when  harvested,  storing,  etc., 
and  the  effect  of  the  same  upon  the  activity  of  the  extract  is  emphasized. 

Eight  per  cent  of  extract  is  reported  as  having  been  obtained  from 
rhizomes  harvested  in  the  spring. 

Kraft,  F.  1902 

Untersuchung  des  Extractum  Filicis. 
Schweiz.    Wochenschr.    f.     Chem.    u.    Pharm.,  40,  p.  322. 
[Chem.  Centralb.,  73,  2,  p.  53;  Pharm.  Ztg.,  48,  p.  275.] 

Two  new  substances  were  isolated  by  the  author  from  the  ethereal  ex- 
tract of  male  fern,  flavaspidin  and  an  amorphous  acid.  The  amorphous  acid  is 
reported  to  be  the  active  principle  and  to  be  present  to  the  extent  of  5  per 
cent,  in  a  good  extract. 

1903 


Table   showing  suggested    standards,    ranges    of    specific 
gravity,  etc.,  for  galencial  preparations. 

Southall  Bros.,  &  Barclay,  Lab.  Rep.,  11,  p.  23. 

The  standard  range  for  the  specific  gravity  of  Extractum  Filicis  Uquidum 
is  given  as  1.000  to  1.019  at  IS.S^C  p.  24.) 


1903 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1903,  p.  77. 
It  is  reported  that  extracts  prepared  from  the  male  fern  rhizomes  har- 
vested during  the  previous  year,  when  assayed  according  to  the  method  of 
Kraft,  yielded  27.08  to  36.6  per  cent,  of  crude  filicin. 


1903 


Ginger. 

Southall  Bros.  &  Barclay,  Lab.  Rep.,  11,  p.  13. 

The  following  table  shows  the  proportion  of  oleoresin  found  in  three 
varieties  of  commercial  ginger. 

Jamaica  Cochin  African 

Per  cent.  sol.  in  alcohol  (90  per  cent.)    4.35  4.57        9.93 

Per  cent.  sol.  in  ether,     Sp.  gr.  0.717      4.76  6.04       11.09 


1903 


Capsicum. 

Southall  Bros.  &  Barclay,  Lab.  Rep.,  11,  p.  13. 

A  sample  of  Capsicum  minimum  yielded  ,5.67  per  cent,  of  material  soluble 
in  ether,  Sp.  gr.  0.717,  and  a  sample  of  Capsicum  annum  yielded  15.34 
per  cent,  to  the  same  solvent. 


BIBLIOGRAPHY  261 

Ballard  1903 

Sur   quelques    condiments   des    colonies   francaise    (Anise 
etoile,  Cannelle,  Cardamome,  Curcurma,  Gingembre,  Girofle. 
Journ.  de  Pharm.  et  de  Chim.,  157,  pp.  248  and  296. 
Ginger  from  the  Ivory  Coast  is  reported  to  have  yielded  6.33  per  cent. 
of  ether  extract,  that  from  Tahiti,  3.75  per  cent,  p.  248. 

Black  pepper  yielded  the  following  percentages  of  extractive  matter 
to  ether:    10.15,   8.70  and  5.50. 

Beythien  1903 

Capsicum. 
Zeitschr.  Unters.  Nahr.  u  Genussm.,  5,  p.  858.     [Pharm. 

Ztg.,  47,  p.  549;  Proc.  A.  Ph.  A.,  51,  p.  747.] 

The  examination  of  a  number  of  commercial  samples  of  powdered  capsi- 

sicum  showed  the  following: 

Yield  of  extract  to  ether  (total)   12.54  to  19.70  per  cent. 

"     <<       <<       <'       "        (av.)    14.94  **      ** 

"     ''       "       '<   alcohol  (total) 26.55  to  35.71    '*      " 

"     "       "       '<       '*        (av.)    28.94  "      " 

Dieterich  1903 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1903,  p.  240. 

Three  samples  of  extract  of  male  fern  examined  showed  a  *' moisture" 
content  of  from  5.52  to  7.38  per  cent,,  and  gave  from  0.27  to  0.39  per 
cent,  of  ash   (p.  241.) 

Penndorff,   O.  1905 

Untersuchungen  ueber  die  Beschaffenheit  kaeuflicher  Filix- 
Ehizoma  und  Extrakte. 
Apoth.-Ztg.,  18,  p.  150. 
The   author  states  that  the  rhizomes  turn  brown  on  aging  due  to  the 
breaking  down  of  the  filix-tannic  acid  into  filix-red  and  sugar. 

An  examination  of  20  samples  of  commercial  rhizomes  showed  that 
12  of  them  or  over  50  per  cent,  contained  rhizomes  of  Aspidium  spinulosum, 
1  sample  consisted  of  90  per  cent,  of  {his  species. 

Twenty  samples  of  commercial  extracts  were  examined  with  the  fol- 
lowing results: 

4  samples  —  Starch  present  in  small  quantities. 
1  sample    — Aspidin   present. 
20  samples  —  6,65  to  18.31  per  cent,   crude   filicin. 
20  samples  — 1.06  to   7.48  per  cent,  filix  acid. 
20  samples  —  0.40  to  3.00  per  cent,  filix  acid  in  solution. 
20  samples  — 0.40  to  6.05  per  cent,  filix  acid  deposited. 
7  samples  —  copper,  more  or  less. 


252  E>U  MEZ— THE  GALENICAL  OLEORESINS 

1904 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1904,  p.  77. 

It  is  stated  that  for  years  the  firm  has  placed  upon  the  market  under 
their  name  an  extract  of  male  fern  containing  not  less  than  29  per  cent. 
of  crude  filicin. 

Dieterich  1904 

Ueber  Extractum  Filicis,  D.  A.  IV. 
Helfenberger  Ann.,  1904,  p.  182. 

The  results  obtained  in  the  examination  of  3  samples  of  the  extract  of 
male  fern  are  tabulated.  The  results  include  the  per  cent,  of  ' '  moisture ' ' 
and  ash,  and  the  iodine  and  saponification  values. 


1905 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1905,  p.  7. 

It  is  stated  that,  although  the  year's  crop  of  male  fern  is  poor,  the  firm 

guarantees  a  crude  filicin  content  of  28  per  cent,  for  their  extract,  (p.  71.) 

Promme's  method  for  estimating  the  crude  filicin  content  is  given  (p.  85.) 

1905 


Ueber     die     wirksamen    Bestandtheile     des     Famwurzel- 
extrakts.    Pharm.  Ztg.,  50,  p.  651. 

The  work  of  Boehm,  also  thai  of  Kraft,  is  commented  on,  special  ref- 
erence being  made  to  Filmaron  isolated  from  the  extract  by  the  latter. 


1905 


The  Newer  Remedies. 

Am.  Drugg.  &  Pharm.  Rec,  46,  p.  135. 


Capsolin  which  is  recommended  as  a  substitute  for  mustard  papers,  is 
said  to  consist  of  a  mixture  of  oleoresin  of  capsicum,  the  oils  of  turpentine, 
cajuput  and  croton,  with  an  ointment  base.  It  is  manufactured  and 
marketed  by  Parke,  Davis  &  Co.,  Detroit. 


1905 


The  New  U.  S.  P.,  Changes  in  Composition  and  Strength. 
Drug  Topics,  20,  p.  210.    [Am.  Journ.  Pharm.,  78,  p.  412.] 

The  new  edition  of  the  U.   S,   P.    specifies    acetone   as   the   solvent    for 
making  all  of  the  oleoresins  with  the  exception  of  oleoresin  of  cubebs,  which 


BIBLIOGRAPHY  263 

is  prepared  with  alcohol.  It  is  stated  that  manufacturers  have  long  since 
seen  the  folly  of  employing  an  expensive  solvent  like  ether,  and  the 
adoption  of  acetone  for  this  purpose  is  a  recognition  of  commercial  phar- 
maceutical advances,   (p.  214.) 

Dieterich  1905 

Extracta  spissa  et  sicca. 
Helfenberger  Ann.,  1905,  p.  159. 

A  sample  of  the  ethereal  extract  of  cubeb,  D.  A.  IV,  showed  a  "mois- 
ture" content  of  55.91  per  cent,  and  an  ash  content  of  0.87  per  cent, 
(p.   160.) 

A  sample  of  extract  of  maje  fern  D.  A.  IV,  gave  a  *' moisture"  content 
of  5.06  per  cent.,  an  ash  content  of  0.46  per  cent,  and  yielded  23.22  per 
cent,  of  crude  filicin    (p.  161.) 

Dieterich  1905 

Khizoma  Zingiberis. 
Helfenberger  Ann.,  1905,  p.  131. 

The  following  percentages  of  extract  were  obtained  by  exhausting  ginger 
with  different  solvents,  evaporating  the  latter  and  dryiag  the  residue  at 
lOO'C: 

1)  One  part  alcohol,  8  parts  water  —  7.86  per  cent. 

2)  Sixty-eight  per  cent,  alcohol  —  4.88  per  cent. 

3)  Ninety  per  cent,  alcohol  —  2.79  per  cent. 

Dieterich  ,  *  1905 

Rhizoma  Filicis. 
Helfenberger  Ann.,  1905,   p.   130. 

During  the  year,  a  number  of  lots  of  male  fern  rhizomes  were  examined. 
The  air-dried  rhizomes  yielded  9.94  to  10.60  per  cent,  of  ethereal  extract. 
The  rhizomes  when  dried  at  lOO^C  yilded  as  high  as  11.20  per  cent,  to 
the  same  solvent. 

Francis,  J.  M.  1905 

The  New  Pharmacopoeia:  A  Detailed  Commentary  on  the 

Eighth  Revision  of  the  U.  S.  P. 

Bull,  of  Pharm.,  19,  p.  317.  [Am.  Joum.  Pharm.,  78,  p.  412.] 

Under  acetone,  it  is  stated  that  oleoresins  prepared  with  this  solvent  will 
separate  in  two  layers  on  standing  owing  to  the  fact  that  this  ketone  pos- 
sesses in  a  measure  the  combined  solvent  properties  of  both  alcohol  and 
ether. 


264  ^^  MEZ— THE  GALENICAL.  OLEORESINS 

Vanderkleed,  C.  E.  1905 

Report  of  the  Committee  on  Adulterations. 
Proe.  Peixna.  Pharm.  Assoc.,  28,  p.  47. 

Eight  assays  of  capsicum  gave  9.4  to  23.9  per  cent,  of  oleoresin,  the 
average  being  18.13  per  cent.  The  standard  for  a  good  drug  is  stated 
to  be  15  per  cent. 

Vieth,  H.  1905 

Ueber   die   Beziehung  zwischen   chemischer  Zusammenset- 

zung  und  medizinisclier  Wirkung  einiger  Balsamika. 

Verh.  d.  Ges.  deutsch.  Naturf.  u.  Aerzte,  2,  p.  364.    [Jah- 

resber.  d.  Pharm.,  66,  p.  13.] 

Kubetenextrakt  is  reported  to  consist  of  terpenes  (65  per  cent.),  resin 
acids  (10  per  cent.),  and  resins  (25  per  cent.) 


1906 


Apiolin 

Merck's  Ann.  Eep.,  20,  p.  34. 

Apiolin  is  the  raw  ethereal  oil  obtained  from  the  seed  of  Petroselinum 
sativum  or  from  Apiol  viride  by  extraction  with  a  suitable  solvent.  It  is  a 
yellow  fluid,  sp.  gr.  1.25  to  1.135,  boiling  at  280  to  300*C. 


1906 


Extractum  Filieis. 

Caesar  and  Loretz,  Geschaefts-Ber.,  Sept.  1906,  pp.  82  and 
99. 

The  firm  reports  that  the  crude  filicin  content  of  the  extract  obtained 
from  the  current  year's  crop  of  male  fern  averages  27  per  cent.   (p.  82). 
Fromme's  method  for  estimating  the  crude  filicin  is  given   (p.  99). 

Naylor,  A.  H.  1906 

Progress  in  pharmacapoeias :    drugs  and  their  constituents* 
Year-Book  of  Pharm.,  43,  p.  204. 

It  is  stated  that  in  the  present  state  of  our  knowledge,  neither  Daccpmo 
and  Scoccianti 's,  Kraft's  nor  Stoeder's  process  for  the  quantitative  esti- 
mation of  filicic  acid  is  a  measure  of  the  anthelmintic  value  of  the  ex- 
tract of  male  fern. 


BIBLIOGRAPHY  265 

Roeder,  Ph.  1906 

Ehizoma  Filicis. 
Jahresb.  d.  Pharm.,  41,  p.  46. 

The  author  states  that  the  rhizomes  of  Aspidium  filix  mas  should  give  at 
most  3  per  cent,  of  ash  and  should  yield  at  least  8  per  cent,  of  extractive 
matter  to  ether,  allowing  the  latter  to  evaporate  spontaneously  and  then 
heating  for  2  hours  at  95  "C,  cooling  in  a  desiccator  and  weighing.  Three 
samples  of  rhizomes  gave  2.52  to  2.92  per  cent,  of  ash,  respectively,  and 
9.22  to  10.1  per  cent,  of  ether-soluble  extract. 

WoUenweber,  W.  1906 

Ueber  Filixgerbsaeure. 
Arch.  d.  Pharm.,  244,  p.  466. 

In  connection  with  his  work  on  the  tannic  acid  in  the  male  fern  rhizomes, 
"the  author  presents  the  results  obtained  in  extracting  the  drug  in  a  Soxh- 
let's  apparatus  with  various  solvents,  ether,  benzol,  and  petroleum  ether. 
At  the  end  of  six  hours,  extraction  was  found  to  be  practically  complete  in 
all  cases.  The  yield  obtained  in  each  case  is  given  as  follows;  ether,  10.0 
per  cent.,  benzol,  9.06  per  cent.,  petroleum  ether,  9.08  per  cent. 

Extraction  with  alcohol  of  varying  strength  yielded  extractive  matter 
in  the  following  quantities:  alcohol  (90  per  cent.),  20.0  per  cent.,  alcohol 
(96  per  cent.),  16.6  per  cent. 

The  fixed  oil  content  of  the  ethereal  extract  is  stated  to  be  70  to  75 
per  cent. 


1907 


Cubebs. 

Evans  Sons  Lescher  &  Webb,  Analyt.  Notes,  1,  p.  21. 

The  oleoresin  extracted  by  ether  from  four  samples  of  cubebs  amounted 
to  (1)  22.08,  (2)  22.6,  (3)  21.13  and  (4)  22.8  per  cent.,  respectively. 


Blome,  W.  H.  1907 

Cubeba. 

Proc.  Mich.  Pharm.  Assoc,  1907,  p.  68.    [Bull.  Hygienic 
Lab.,  No.  63,  p.  225.] 

Five  samples  of  cubeb  are  reported  which  assayed  from  18.85  to  26.88 
per  cent,  of  oleoresin. 


266 


DU  MBZ— THE  GALENICAL  OLEORESINS 


Van  der  Harst,  J.  C.  1907 

Lupulin. 
Pharm.  AVeekbl.,  44,  p.  1506.    [Bull.  Hygienic  Lab.,  No.  63, 

p.  301.] 

Two  samples  of  lupulin  were  found  to  contain  52  and  65  per  cent,  of 
ether-soluble  matter,  respectively. 

Patch,  E.  L.  1907 

Report  of  Committee  on  Drug  Market. 
Proc.  Am.  Pharm.  Assoc,  55,  p.  314. 

The  samples  of  capsicum  examined  yielded  from  16.2  to  26.5  per  cent, 
of  alcoholic  extract  (p.  324.) 

Smith,  0.  W.  1907 

Galenicals  of  the  U.  S.  P.  VIII. 
Proc.  Mo.  Pharm.  Assoc,  29,  p.  132. 

The  author  is  of  the  opinion  that  the  oleoresin  of  eubeb  might  well  have 
been  included  in  the  class  made  with  acetone,  as  the  drug  yields  but  little 
on  subsequent  extraction  with  alcohol.  Alcohol  on  the  other  hand  is 
/Open  to  the  objection  that  its  boiling  point  is  so  high  that  a  considerable 
loss  of  volatile  substances  from  the  cubeb  occurs  when  the  solvent  ia 
evaporated  (p.  134.) 


1908 


Extractum  Filicis. 

Caesar  and  Loretz,    Geschaefts-Ber.,    Sept.    1908,    pp.    76 

and  99. 

It  is  stated  that  for  years  the  firm  has  estimated  the  crude  filicin  con- 
tent of  the  extract  of  male  fern  and  marketed  a  standard  product  contain- 
ing 28  per  cent,  of  this  constituent  as  required  by  the  Swiss  PharmacopcEia, 
VI,    (p.  76.) 

Fromme's  method  for  estimating  the  crude  filicin  is  given  (p.  99.) 


Dohme  and  Engelhardt  1908 

Purity  of  some  official  and  non-official  drugs  and  chemicals. 
Proc  Am.  Pharm.,  Assoc,  56,  p.  814. 

A  sample  of  lupulin  yielding  only  56  per  cent,  of  ether-soluble  matter  is 
reported  (p.  817.) 


BIBLIOGRAPHY  267 

Patch,  E.  L.  1908 

Report  of  Committee  on  Drug  Market. 

Proc.  Am.  Pharm.  Assoc.,  56,  p.  765. 
The  different  samples  of  capsicum  examined  yielded  from  15  to  25.2  per 
cent,  of  alcoholic  extract  (p.  768.) 

Spaeth,  Eduard  1908 

Die    chemische    und    mikroskopische    Untersuchung    der 

Gewiirze  und  deren  Berurteilung. 
Pharm.  Centralh.,  49,  p.  581. 

The  paper  discusses  the  characteristics  of  several  commercial  varieties 
of  ginger  and  the  composition  of  the  drug.  The  quantity  of  material 
extracted  by  ether,  alcohol,  petroleum  ether  and  methyl  alcohol  is  given. 

Vanderkleed,  C.  E.  1908 

Report  of  Committee  on  Adulteration. 
Proc.  Penna.  Pharm.  Assoc,  31,  p.  65. 

Three  samples  of  capsicum  yielded  from  11.59  to  18.35  per  cent,  of  oleo- 
resin;  four  samples  of  cubebs,  16.39  to  23.6  per  cent;  two  samples  of 
ginger,  5.58  to  9.55  per  cent;  three  samples  of  male  fern,  6.68  to  17.9  per 
cent.,  average  10.002  per  cent.  (p.  88.) 

1909 


Pharmacy  Committee's  Report. 
Chem.  &  Drugg.,  74,  p.  288. 

The  Committee  of  Reference  in  Pharmacy  asserts  that  cubebs  should 
yield  not  less  than  20  per  cent,  of  oleoresin  to  ether,  sp.  gr.  not  over 
0.720.     (p.  292.) 

1909 


Extractum  Filicis. 

Caesar  and  Loretz,  Geschaefts-Ber.  Sept.  1909,  pp.  67  and  84. 

A  crude  filicin  content  of  28  per  cent,  is  guaranteed  by  the  firm  for  the 
new  lot  of  extract  of  male  fern  (p.  67.) 

Fromme's  method  for  the  estimation  of  the  crude  filicin  is  given  (p.  84.) 

1909 


Apiol. 

Evans  Sons  Lescher  &  Webb,  Analyt.  Notes,  4,  p.  11. 

A  sample  of  apiol  of  French  manufacture  examined  by  the  firm  is  re- 
ported as  having  been  liquid  and  green  in  color.      It  yielded  40  per  cent,  of 


268 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Its  bulk  to  steam  distillation.  It  is^  therefore,  thought  that  the  sample 
was  prepared  by  the  extraction  of  parsley  fruits  with  a  suitable  light 
solvent.  ' 


Bernegau,  L.  H.  1909 

Report  of  the  Committee  on  Adulteration. 
Proe.  Penna.  Pharm.  Assoc,  32,  p.  119. 

Ten  samples  of  lupulin  examined  yielded  from  34  to  65.8  per  cent,  of 
ether-soluble  matter  (p.  125.) 


Dohme  and  Engelhardt  1909 

Purity  of  some  official  and  non-official  drugs  and  chemicals. 
Proc.  A.  Ph.  A.,  Assoc,  57,  p.  713. 

*     Three  samples  of  lupulin   examined    were    low   in    ether-soluble    matter 
yielding  but  47.50,  and  43  per  cent.,  respectively    (p.   716.) 

Dunn,  J.  A.  1909 

Suggested  Modifications  of  U.  S.  P.  and  N.  F.  Formulas. 
Proc  A.  Ph.  A.,  57,  p.  942. 

It  is  stated  that  the  oleoresin  of  male  fern  prepared  by  the  TJ.  S.  P. 
method,  using  acetone,  contains  so  much  undesirable  extractive  matter  that 
it  is  necessary  to  purify  it  by  dissolving  in  ether.  It  is  suggested  that  it 
might  be  worth  while  to  consider  whether  the  U.  S.  P.  should  not  go 
back  to  the  use  of  ether   (p.  949.) 

Parson,  W.  A.  1909 

Report  of  the  Committee  on  Adulteration. 
Proc  Penna.  Pharm.  Assoc,  32,  p.  119. 

Three  samples  of  lupulin  yielded  66.1  and  54  per  cent,  of  ether-soluble 
matter,  respectively  (p.  125.) 


Patch,  E.  L.  1909 

Report  of  Committee  on  Drug  Market. 
Proc  A.  Ph.  A.,  57,  p.  721. 

The  alcoholic  extract  from  specimens     of    ginger    examined  varied  from 
3.7  to  6.2  per  cent.  (p.  739.) 


BIBLIOGRAPHY  269 

Vanderkeed,  C.  A.  1909 

Report  of  the  Committee  on  Adulteration. 
Proc.  Penna.  Pharm.,  Assoc.,  32,  p.  119. 

Samples  of  capsicum,  cubebs,  ginger,  and  male  fern  examined  are  re- 
ported to  have  yielded  oleoresin  as  follows:  five  samples  of  capsicum,  14.34 
to  17.95  per  cent;  four  samples  of  cubebs,  16.49  to  24.34  per  cent;  sixteen 
samples  of  Jamaica  ginger,  3.142  to  6.91  per  cent;  two  samples  of  African 
ginger,  8.2  and  9.036  per  cent;  one  sample  of  male  fern,  10.33  per  cent, 
(p.  129.) 


i9ia 


Extr actum  Filicis. 

Caesar  and  Loretz,  Jahres-Ber.,  Sept.  1910,  p.  90. 

Fromme's  method  for  the  estimation  of  crude  filicin  is  given. 


1910 


Cubebs. 

Southall  Bros.  &  Barclay,  Lab.  Rep.,  17,  p.  11. 


Eight  samples  of  cubebs,  when  extracted  with  petroleum  spirits,  yielded 
from  3.88  to  18.08  per  cent,  of  extractive  matter.  The  same  samples  on- 
subsequent  extraction  with  alcohol  (90  per  cent.)  yielded  from  3.4  to  5.6(ii 
per  cent,  of  extractive  matter. 


1910 


Capsicum. 

Southall  Bros.  &  Barclay,  Lab.  Rep.,  17,  p.  8. 

Two  samples  of  capsicum  (B.  P.  C.)  yielded  15.4  and  14.0  per  cent., 
respectively,  of  extract  to  benzol. 


Dohme  and  Engelhardt  1910 

The  new  Hungarian  Pharmacopoeia. 
Proc.  Am.  Pharm.  Assoc,  58,  p.  1168. 

The  extraction  of  male  fern  with  ether,  as  directed  in  the  Ph.  Hung.  Ill, 
instead  of  acetone  as  in  the  U.  S.  P.,  VIII,  is  thought  to  be  desirable  since 
the  latter  is  liable  to  extract  substances  which  might  produce  injurioni 
after  effects  (p.  1179.) 

It  is  further  stated  that  the  yield  of  ether  extract  as  given  in  the  Hun- 
garian Pharmacopoeia  is  8  per  cent.  (p.  1184.) 


nfQ  DU  MEZ— THE  GALENICAL  OLEORESINS 

Eldred,  F.  R.  1910 

Some  data  obtained  in  the  examination  of  official  substances. 
Proc.  A.  Ph.  A.,  58,  p.  889. 

Forty-eight  lots  of  capsicum  were  examined.  The  yield  of  ether-soluble 
oleoresin,  when  the  latter  was  dried  for  one  hour  on  a  water  bath,  was 
found  to  vary  from  11  to  26  per  cent.,  the  average  18  per  cent.  (p.891.) 

Gane,  E.  H.  1910 

Pharmacopoeial  notes  and  comments. 
Drug  Topics,  25,  p.  212. 
It  is  stated  that  a  good  sample  of  cubebs  should  yield  20  per  cent,  of 
ether-soluble  extract. 

Gane  and  Webster  1910 

Pharmacopoeial  notes  and  comments. 

Drug  Topics,  25,  p. 
Aspidium  is  stated  to  be  one  of  the  most  useful  of  drugs  when  carefully 
collected  and  preserved,  but  that  much  of  the  rhizome  is  inert  and  is  ob- 
tained from  any  old  species  of  fern.  It  is  said  to  be  falling  into  disuse 
on  this  account.  It  is  thought  that  the  observance  of  more  care  in  the 
collection  of  the  drug  and  the  preparation  of  the  oleoresin  would  restore 
•its  popularity  as  an  anthelmintic. 

La  Wall,  C.  H.  1910 

Some  suggested  standards  and  changes,  for  the  U.  S.  P. 
Am.  Joum.  Pharm.,  82,  p.  21. 

The  author  asserts  that  a  test  for  capsicum  should  be  included  in  the 
U.  S.  P.  requirements  for  the  oleoresin  of  ginger  as  many  commercial 
samples  used  in  making  ginger  ale  extracts  contain  oleoresin  of  capsicum 
and  these  occasionally  find  their  way  into  the  pharmaceutical  trade. 

A  method  for  the  detection  of  capsicum  in  the  oleoresin  of  ginger  based 
on  the  neutralization  of  the  pungent  principle  of  the  ginger  with  potassium 
hydroxide  is  described  (p.  25.) 

Vanderkleed,  C.  E.  1910 

Report  of  the  Committee  on  Adulterations. 
Proc.  Penna.  Pharm.  Assoc,  33,  p.  131. 
Seven     samples  of  capsicum  yielded  from  15.10  to  22.27   per   cent,  of 
oleoresin;   one  sample  of  African  ginger  10.12  per  cent;  two  samples  of 
Jamaica  ginger  5.636  and  6.316  per  cent.,  respectively  (p.  147.) 


BIBLIOGRAPHY  271 

1911 

Extractum  Filicis. 

Caesar  and  Loretz  Jahres.-Ber.,  Aug.  1911,  pp.  76  and  105. 

Eegret  is  expressed  in  that  the  Ph.  Germ.  V.  has  not  included  an  assay 
for  oleoresin  of  aspidium.  The  crude  filicin  content  is  thought  to  be  a 
satisfactory  indication  of  the  value  of  this  preparation.  A  filicin  con- 
tent of  27  per  cent,  is  guaranteed  by  the  firm  for  the  new  lot  of  the  ex- 
tract prepared  by  them   (p.  76.) 

Fromme's  method  of  estimating  the  crude  filicin  is  given  (p.  105.) 

1911 


Male  fern  extract. 

Evans  Sons  Lescher  &  Webb,  Analyt.  Notes,  6,  p.  48. 

Five  samples  of  male  fern  extract  were  tested.  Two  were  found  to 
be  adulterated  with  castor  oil  (55  to  70  per  cent.) 

The  Kraft  and  the  Swiss  pharmacopoeial  methods  for  evaluating  the 
extracts  are  discussed  and  the  results  obtained  in  each  case,  along  with  other 
physical  and  chemical  constants,  are  tabulated. 

1911 


Cubebs. 

Southall  Bros.  &  Barclay  Lab.  Rep.,  19,  p.  9. 

Five  samples  of     cubebs  yielded  from  4.66  to  8.78  per  cent,  of  extract 
to  petroleum  spirit,  the  average  being  6.95  per  cent. 

: 1911 


Insect  Powder. 

Southall  Bros.  &  Barclay,  Lab.  Rep.,  19,  p.  10. 

Two  samples  of  insect  powder  yielded  8.28  and  7.57  per  cent,  of  oleo 
resin  when  tested  by  Durant's  method. 

One  sample  of  Japanese  insect  flowers  yielded  13.98  per  cent,  of  oleo- 
resin of  an  orange  brown  color. 


1911 


Oil  of  male  fern. 

Brit.  &  Col.  Drugg.,  60,  p.  388. 


In  this  article,  it  is  stated  that  parcels  of  the  extract  of  male  fern  are 
being  condemned  in  London  as  they  have  been  found  to  contain  large 
quantities  of  castor  oil. 

Suspicion    was    first     aroused     through     the    low  selling  price  of  some 


272  DU  MEZ — THE  GALENICAL.  OLEORESINS 

of  the  extracts.-  The  adulterated  extract  was  being  sold  for  4s  per 
pound  while  reliable  manufacturers  would  not  quote  prices  below  5  s  6  d 
per  pound. 

1911 


Ext.  Filicis  maris. 

Chem.  &  Drugg.,  79,  p.  749  and  798. 

This  editorial  commenting  on  Parry's  observation,  that  extract  of  male 
fern  is  commonly  adulterated  with  castor  oil,  calls  attention  to  the  testj* 
given  in  the  Netherlands  and  Swiss  pharmacopoeias. 

Bernegau,  L.  H.  1911 

Keport  of  the  Committee  on  Adulterations. 
Proc.  Penna.  Pharm.  Assoc.  34,  p.  117. 

Three  lots  of  lupulin  tested  58.9,  57.7  and  62.1  per  cent,  soluble  in 
ether   (p.  125.) 

Beythien,  Hemple  &  Others  1911 

Kurze  Mitteilungen  aus  der  Praxis  des  Chemischen  Unter- 

siichungsamtes  der  Stadt  Dresden. 

Zeitschr.  Unters.  Nahr.  u.  Genussm.,  21,  p.  666. 

A  table  is  presented  showing  the  ash  content  and  extract  content  of  a 
number  of  samples  of  ginger   (p.  668.) 

According  to  Eeich  the  volatile  ether  extract  content  varied  from  0.80 
to  4.02  per  cent.,  the  non  volatile  from  1.66  to  6.93  per  cent;  the  alcoholic 
extract  from  1.33  to  4.08  per  cent;  the  petroleum  ether  extract  from  1.14 
to  4.49  per  cent;  and  the  methyl  alcohol  extract  from  4.40  to  12.53  per 
cent. 

Deane,  Harold  1911 

Oleoresina  Capsici,  B.  P.  C. 
Pharm.  Journ.,  87,  p.  804. 

The  author  criticises  the  British  Pharmaceutical  Codex  with  respect  to 
the  title  Oleoresina  Capsioi.  He  is  of  the  opinion  that  the  preparation 
has  no  right  to  the  name  oleoresin,  as  it  corresponds  more  closely  to  the 
product  sold  as  capsicin  or  soluble  capsicin  for  the  use  of  pill  makers 
and  mineral  water  manufacturers. 

Francis,  J.  M.  1911 

Report  of  the  Committee  on  Adulterations. 
Proc.  Penna.  Pharm.  Assoc,  34,  p.  117. 

Only  one  of  eight  lots  of  lupulin  examined  failed  to  exceed  the  required 
60  per  cent,  of  ether-soluble  matter  (p.  125.) 


,    BIBLIOGRAPHY  273 

Glueeksmann,  G.  1911 

Ueber  eine  neue  Identitaetsreaktion  des  Extractum  Cube- 

barum. 

Pharm.  Praxis,  1911,  p.  98.    [Apoth.-Ztg.,  27,  p.  334.] 

A  test  in  which  hydrochloric  acid  is  used  fo^  producing  a  color  reaction 
is  described  in  detail. 

Parry,  E.  J.  1911 

Extract  of  male  fern. 

Pharm.  Journ.  87,  p.  778.    [Chem.  &  Drugg.,  79,  p.  860; 
Am.  Journ.  Pharm.,  84,  p.  136;  Apoth-Ztg.,  26,  p.  1046.] 

The  author  reports  on  the  examination  of  commercial  extracts  of  male 
fern  and  finds  that  the  greater  part  are  undoubtedly  adulterated  with  from 
30  to  60  per  cent,  of  castor  oil.  The  physical  and  chemical  constants 
of  the  commercial  samples  and  of  genuine  extracts  are  tabulated  for  com- 
parison. 

Pearson,  W.  A.  1911 

Report  of  the  Committee  on  Adulterations. 
Proc.  Penna.  Pharm.  Assoc,  34,  p.  126.    [Bull.  A.  Ph.  A., 

6,  p.  346.] 

The  author  reports  that  two  lots  of  oleoresin  of  aspidium  were  rejected 
because  they  were  not  green  in  color. 

Rosendahl,  H.  V.  1911 

Fern  rhizomes,  yield  of  extract  and  relative  activity  of. 
Year-Book  of  Pharm.,  48,  p.  286.    [Apoth.-Ztg.,  26,  p.  588 ; 

Svensk.  farmac.  Tidsk.,  1911,  p.  85.] 

The  yield  of  ethereal  extract  obtained  from  various  species  of  ferm 
harvested  during  different  months  of  the  year  was  found  to  be  as  follows: 


Aspidium  filix  mas 

Dryopteris  spinulosa 

Dryopteris  dliatata 

Fteris  aquUina 

Athyrium  filix  femina 

Aspidium  alpestris 
Two  grams  of  the  extract  of  Dryopteris  dilataia  are  stated  to  be  thera- 
peutically equivalent  to  8  to  10  grams  of  the  extract  of  Aspidium  filix  maa 
or  four  grams  of  the  extract  of  Dryopteris  spinulosa. 


May 

August 

October 

Per  cent. 

Per  cent. 

Per  cent. 

— 

12.5 

11.0 

— 

17.0 

— 

10.0 

— 

— 

2.0 

— 

— 

0.9 





0.7 

__ 

«_ 

>274  I5U  MEZ— THE  GALENICAL  OLEORESINS 

Vanderkleed,  C.   E.  1911 

Eeport  of  the  Committee  on  Adulterations. 
Proc.  Penna.  Pharm.  Assoc.,  34,  p.  117. 

Two  samples  of  capsicum  are  reported  to  have  yielded  14.7  to  17.93  per 
^ent.,  respectively,  of  oleoresin;  one  sample  of  subebs,  22.14  per  cent; 
eleven  samples  of  African  ginger,  7.128  to  9.484  per  cent;  and  eight 
samples  of  Jamaica  ginger,  3.4  to  6.6  per  cent.   (p.  132.) 

1912 


Extractum  Filicis. 

Caesar  and  Loretz,  Jahres-Ber.,  Sept.  1912,  p.  128. 

The  firm's  method  for  estimating  the  crude  filicin  is  given. 


1912 


Capsicine. 

Evans  Sons  Lescher  &  Webb,  Anaylt.   Notes,  7,  p.  18. 

Five  samples  of  capsicvne  examined  were  all  entirely  soluble  in  10  vol- 
lunes  of  90  per  cent,  alcohol. 


1912 


Male  fern  extract. 

Evans  Sons  Lescher  &  Webb,  Analyt.  Notes,  7,  p.  51. 

Sixteen  samples  of  male  fern  extract  examined  in  1912  were  free  from 
castor  oil  and  of  satisfactory  purity.  They  showed  a  refractive  index  of 
1.507  to  1.509  at  15''C,  and  gave  a  filicin  content  of  22.9  to  26.3  per  cent., 
when  assayed  according  to  the  method  given  in  the  Swiss  Pharmacopoeia. 


1912 


Capsicum. 

Johnson  &  Johnson,  Lab.  Notes,  1912,  p.  14. 


The  yield  of  ether  extract  obtained  from  capsicum  is  reported  to  have 
varied  from  16  to  19  per  cent. 


1912 


Cheap  extract  of  male  fern  found  badly  adulterated. 
Merck's  Eeport,  21,  p.  29  [Apothecary,  24,  p.  14.] 

A  sample  of  cheap  extract  of  male  fern  examined  by  Merck  was  found 
to  be  adulterated  with  25  per  cent,  of  castor  oil,  and  to  contain  only  8  per 
cent,   of   crude  filicin. 


BIBLIOGRAPHY  275 

1912 

Male  fern  extract. 

Southall  Bros.,  &  Barclay,  Lab.  Kep.,  20,  p.  15. 

The  statement  of  Parry  that  much  of  the  male  fern  extract  is  adulterated 
is  confirmed.  The  physical  and  chemical  constants  obtained  in  the  ex- 
amination of  six  commercial  extracts  are  tabulated. 

Dohme  and  Engelhardt  1912 

Drug  quality  during  the  period  1906-1911. 
Journ.  A.  Ph.  A.,  1,  p.  99. 

It  is  stated  that  there  was  hardly  any  variation  in  the  percentage  of 
oleoresin  in  the  samples  of  cubebs  examined  during  the  last  six  years, 
(p.  101.) 

Goris  and  Voisin  1912 

The  determination  of  the  ether  extract  of  male  fern,  and  the 
unification  of  the  methods  of  analysis. 

Bull.  Sci.  Pharmacolog.,  19,  p.  705,   [Pharm.  Ztg.,  58,  p. 
129;  Journ.  90,  p.  81;  Year-Book  of  Pharm.,  50,  p.  337.] 

It  is  stated  that  the  method  of  the  Swiss  Codex  gives  values  for  crude 
filicin  which  are  about  30  per  cent,  too  high  owing  to  the  solubility  of 
the  ether  solution  in  '  the  solution  of  barium  hydroxide.  If  the  ether  be 
driven  off  by  heating  to  50  °C  before  filtering,  the  results  will  be  com- 
parable with  those  obtained  by   the  magnesia  methods. 

Hooper,  D.  1912 

Notes  on  Indian  drugs. 
Pharm.  Journ.  89,  p.  391. 

The  examination  of  the  rhizomes  of  Indian  ginger,  with  reference  to  de- 
termining the  relationship  between  maturity  and  oleoresin  content,  showed 
that  young  rhizomes  develop  oleoresin  as  they  are  allowed  to  grow.  Those 
gathered  in  December  yielded  6.4  per  cent,  of  extract  to  alcohol  (90  per 
cent.),  while  those  gathered  in  February  gave  8.3  per  cent.  Upon  washing 
the  extracts  with  water,  the  remaining  insoluble  residue  amounted  to  3.0 
per  cent,  and  3.5  per  cent.,  respectively.  Some  of  the  more  mature  rhizomes 
gave  as  high  as  11.8  per  cent,  of  alcoholic  extract  or  8.1  per  cent,  of 
washed  resin. 

Patch,  E.  L.  1912 

Report  of  the  Committee  on  Drug  Market. 
Journ.  A.  Ph.  A.,  1,  p.  499. 

Eight  samples  of  Jamaica  ginger  gave  from  3.3  to  6.0  per  cent,  of  alco- 
holic extract  (p.  500.) 


276  DU  MEZ— THE  GALENICAL  OLEORESINS 

V'anderkleed,  C.  E.  1912 

Report  of  Committee  on  Drug  Market. 
Proe.  Penna.  Pharm.  Assoc.,  35,  p.  165. 
The  assay  of  4  samples  of    capsicum  showed  the  oleoresin  content  to  ba 
from  14.41  to  16.7  per  cent;  five  samples  of  cubebs  yielded  1.735  to  24.49 
per  cent,  of  oleoresin;  seventeen  samples  of  Jamaica  ginger,  3.444  to  6.b'4<> 
per  cent;  ten  samples  of  African  ginger,  6.85  to  11.10  per  cent  (p.  179.) 


1913 


Miscellaneous  Inquiries.   • 
Chem.  &  Drugg.,  82,  p.  470. 
Gingerin  is  stated  to  be  the  extract  obtained  upon  evaporating  the  tinc- 
ture of  ginger.     It  is  said  to  vary  with  the  variety  of  ginger  used  in  the 
preparation  of  the  tincture. 

Capsicin  is  stated  to  be  commercially  indefinite.  It  may  be  a  strong  alco- 
holic extract,  an  ethereal,  a  chloroformic  or  an  acetone  preparation.  The 
accepted  capsicin  of  commerce,  however,  is  the  oleoresin  prepared  with 
ether. 


1913 


Die  Methoden  zur  Wertbestimmung  des  Filixextrakts. 
Pharm.  Ztg.,  58,  p.  129. 
The  methods  of  Goris  and  Voisin,  and  E.  Schmidt  for  the  evaluation  of 
the  extract  of  male  fern  are  discussed. 


1913 


Extractum  Filicis. 

Caesar  and  Loretz,  Jahres.-Ber.,  Sept.  1913,  pp.  98  and  106. 
Four  samples  of  extract  of  male   fern  prepared  by  the  firm  showed  a 
crude  filicin  content  of  32.64,  23.7,  28.15  and  30.4  per  cent.,  respectively, 
(p.  98.) 

The  firm  guarantees  the  filicin  content  of  their  extract  to  be  27  per 
cent. 


1913 


Male  fern  extract. 

Evans  Sons  Lescher  &  Webb,  Analyt.  Notes,  8,  p.  44.   [Year- 
Book  of  Pharm.,  51,  p.  244.] 

Seven  samples  of  extract  of  male  fern  examined  during  the  year  showed 

a  filicin  content  of  21.3  to  25.3  per  cent,  and  a  refractive  index  of  1.5  to  1.51. 

Three  eamples  were  impure  or  suspicious.       They  showed  a  refractive 

index  of  1.495,  1,497  and  1.499,  and  a  filicin  content  of  15.6,  19.6  and 

19.7  per  cent.,  respectively. 


BIBLIOGRAPHY  277 
1913 

Male  fern  extract. 

Southall  Bros.,  &  Barclay,  Lab.  Rep.,  21,  p.  14. 

The  analytical  data  obtained  in  the  examination  of  two  commercial 
samples  of  the  extract  of  male  fern  are  given. 

Bohrisch,  P.  1913 

Ueber  Extractum  Filicis. 
Pharm.  Ztg.,  58,  p.  601.     [Chem.  Abs.  8,  p.  206.] 

A  comprehensive  review  of  the  constituents  and  the  methods  of  evaluat- 
ing the  extract  of  male  fern  is  given. 

Four  samples  of  commercial  extracts  in  bulk  were  examined  for  density 
and  crude  filicin  content.  The  findings  for  density  were  0.9888,  0.9842, 
0.9836  and  1.0109;  for  crude  filicin  14.85;  15.42,  16.00  and  24.00  per  cent. 
The  same  tests  for  five  samples  of  the  extract  in  capsules  showed:  density, 
0.9824,  not  determined,  1.0135,  1.0255  and  0.9910;  crude  filicin,  15.02, 
23.42,  26.77,  27.72  and  14.45  per  cent. 

Dobme  and  Engelhardt  '  1913 

Cubebs. 

Oil,  Paint  and  Drug  Rep.,  83,  p.  55. 
The  quantities   of   oleoresin   obtained   from  cubebs   ranged  between    16 
and  22  per  cent. 

DuMez,  A.  G.  1913 

The  physical  and  chemical  properties  of  the  oleoresin  of  As- 

pidium  with  respect  to  the  detection  of  adulterations. 
Philippine  Journ.  of  Sc,  8,  Sec.  B.,  p.  523. 

The  methods  of  adulterating  the  oleoresin  are  discussed  in  detail  The 
physical  and  chemical  constants  of  samples  prepared  in  the  laboratory  and 
those  obtained  from  various  commercial  sourcee  are  presented  with  the 
idea  of  indicating  to  what  extent  they  may  be  relied  upon  in  detecting 
a  deteriorated  or  adulterated  product. 

Engelhardt,  H.  1913 

Purity  of  chemicals  and  drugs. 

Journ.  A.  Ph.  A.,  2,  p.  163. 
Four  samples  of  black  pepper  are  reported  to  have  yielded  10.6,  If^.S, 
9.2  and  11  per  cent.,  respectively,  of  oleoresin;  six  samples  of  capsicum, 
13.1,  41.8,  15.26,  15,8,  11.3  and  11  per  cent;  cubebs  from  18  to  25  per 
cent;  Jamaica  ginger  from  2.81  to  5.24  per  cent;  lupulin,  eight  samples 
out  of  twelve,  less  than  60  per  cent;  three  samples  of  parsley  seed.  14.7, 
11.4  and  13.04  per  cent.      (pp.  164  and  165.) 


278  I^U  MEZ — THE  GALENICAL  OLEORESINS 

Gane,  E.  H.  1913 

Report  of  Committee  on  Drug  Market,  August,  1912. 
Journ.  A.  Ph.  A.,  2,  p.  677. 

Four  lots  of  lupulin  gave  44.94  to  65.5  per  cent,  of  ether-soluble  material,. 

(p.  681.) 


Harrison  and  Self.  1913 

Analytical  constants  of  extract  of  male  fern. 
Chem.  &  Drugg.  83,  p.  182.    [  Year-Book  of  Pharm.,  50,  p. 

494 ;  Pharm.  Journ.  91,  p.  128 ;  Pharm.  Ztg.,  58,  p.  643.] 

The  analytical  constants  of  genuine  and  commercial  extracts  of  mala 
fern  are  tabulated.  The  authors  do  not  approve  of  the  standards  sug- 
gested by  Parry. 

Hm,  C.  A.  1913 

Analytical  notes  on  extract  of  male  fern. 

Chem.  &  Drugg.,  83,  p.  181.     [Pharm.  Ztg.,  58,  p.  643.] 

The  analytical  constants  of  23  samples  of  extract  of  male  fern  are 
discussed  and  tabulated.  The  chemical  and  physical  constants  of  the  oily 
portion  are  also  given  for  comparison  with  those  of  castor  oil.  One  com- 
mercial sample  is  reported  to  have  contained  59  per  cent,  of  the  latter. 

Osborne,  Oliver  F.  1913 

A  last  plea  for  a  useful  Pharmacopoeia. 
Journ.  Am.  Med.  Assoc,  60,  p.  1427. 

Among  the  ''useless"  preparations  adopted  by  the  Committee  of  Re- 
vision, the  author  includes  the  oleoresins  of  lupulin  and  parsley  seed^ 
(p.   1429.) 

Parry,  E.  J.  1913 

Extract  of  male  fern. 
Chem.  &  Drugg.,  83,  p.  231. 
The  author  confirms  the  results  which  he  published  in  an  earlier  paper. 

Patch,  E.  L.  1913 

Report  of  the  Committee  on  Drug  Market. 
Journ.  A.  Ph.  A.,  2,  p.  1081. 

The  percentage  of  alcoholic  extract  obtained  from  the  drugs  tested  is 
reported  as  follows: 


BIBLIOGRAPHY  279^ 

Capsicum,  four  samples,  19  to  24  per  cent;  ginger,  nine  samples,  5.2, 
5.7,  4.2,  4.0,  4.5,  4.9,  3.5,  4.8  and  4.3  per  cent.  pp.  1088  and  1094. 
The  yield  of  ether  extract  reported  by  Kebler  is  as  follows: 
Fifty-three  samples,  lupulin,  63.96  to  77..82  per  cent;  black  pepper 
three  lots,  10.04,  10.87  and  12.88  per  cent;  red  pepper,  eight  samples, 
13.0,  10.6,  14.7,  18.91,  13.12,  10.4,  13.25  and  14.7  per  cent.  The  iodine^ 
values  for  the  same  were  132,  138,  123.4,  107,  127.3,  25.2  and  137.3. 
Seventeen  other  samples  yielded  from  11.22  to  20.77  per  cent.  The  iodine 
value  of  these  varied  from  110  to  145.7   (pp.  1098  and  1101.) 

Umney,  J.  C.  1913 

What  is  capsicin? 

Pharm.  Journ.,  91,  p.  594. 
Capsicin  is  stated  to  be  a  synonym  for  Oleo-Besin  of  Capsicum  of  the 
B.  P.  Codex,  and,  is  made  by  extracting  capsicum  with  60  per  cent.  alcohoL 
and  subsequently  evaporating  off  the  solvent.  It  should  not  be  con- 
fused with  the  preparations  made  with  strong  alcohol  (90  per  cent.)^ 
ether  or  acetone. 

Vanderkleed,  C.  E.  1913 

Report  of  the  Committee  on  Drug  Market. 
Proc.  Penna.  Pharm.  Assoc,  36,  p.  77. 
Thirty-seven  samples  of   Jamaica  ginger   are  reported  to  have  yielded 
3.10  to  5.75  per  cent,  of  oleoresin;  seventeen  samples  of  African  ginger,, 
6.85  to  9.92  per  cent;  seven  samples  of  capsicum,  13.1  to  18.1  per  cent;, 
one  sample  of  cubebs,  21.8  per  cent. 

Yagi,  S.  1913 

Physiologische  Wertbestimmung  von  Filixsubstanzen  nnd' 

Filixextrakten. 

Zeitschr,  f.  d.  ges.  exp.  Med.,  3,  p.  64.     [Therap.  Monatsch.,. 

1914,  p.  443;  Apoth-Ztg.,  29,  p.  544.] 
A  method  in  which  earth  worms  are  used  for  the  purpose  of  testing  the- 

relative  activity  of  extract  of  male  fern  and  its  constituents  is  described. 

1914 


Untersuchung  der  offizinellen  vegetablischen  Drogen. 
Riedel's  Ber.  58,  p.  29. 

The  samples  of  cubebs  examined  are  reported  as  having  yielded  11.1  to- 
14.7  per  cent,  of  extract  soluble  in  ether  1  part  and  alcohol  1  part  (p.  31.) 

The  alcohol  extract  obtained  from  capsicum  varied  from  31.9  to  35.3- 
per  cent.   (p.  32.) 

The  samples  of  aspidium  examined  gave  9.4  to  9.7  per  cent,  of  ether- 
soluble  extract. 


DU  MEZ— THE  GALENICAL.  OLEORESINS 

1914' 


Ueber  Gelatinkapsel-Fabrikate. 

RiedePs  Ber.  58,  p.  45.     [Apoth.-Ztg.,  29,  p.  310.] 

Capsules  from  only  two  manufacturers  contained  extract  of  male  fern 
of  which  the  crude  filicin  content  was  higher  than  20  per  cent.  The  ex- 
tract of  male  fern  in  capsules  from  four  other  sources  showed  a  filicin 
content  of  from  8.57"  to  16.02  per  cent.    (p.  48.) 


1914 


Extractum  Filicis. 

Caesar  and  Loretz,  Jahres-Ber.,  Oct.,  pp.  23,  37,  and  96. 

The  method  of  S.  Yagi  for  the  physiological  standardization  of  the  extract 
of  male  fern  is  stated  to  be  too  cumbersome  for  practical  use.  (p.  23.) 

Extracts  prepared  in  the  laboratory  showed  the  following  crude  filicin 
content,  25.48,  24.85,  29.7,  26.04,  26.0,  35.58,  27.35  and  33.79  per  cent, 
(p.  37.) 

It  is  further  stated  that  the  yield  of  ether  extract,  after  evaporating  on 
&  water  bath  at  60 °C  to  constant  weight  and  drying  in  a  desiccator  for 
half  an  hour,  should  be  about  15  to  18  per  cent.    (p.  96.) 


1914 


United  States  Pharmacopoeia  Ninth  Kevision.  Abstracts  of 
proposed  changes  with  new  standards  and  descriptions. 

Journ.  A.  Ph.  A.,  3,  pp.  524  and  1573.  [Year-Book  of 
Pharm.,  52,  p.  324.] 

It  is  stated  that  the  former  solvent,  acetone,  is  to  be  changed  to  ether 
in  the  following:  Oleoresina  Aspidii,  Oleoresina  Capsici,  Oleoresina 
Zingiheris  and  Oleoresina  Piperis.     (p.  551.) 

Directions  are  also  given  for  the  preparation  of  Oleoresina  Petroselini 
(p.    573.) 

Bohrisch,  P.  1914 

Ueber    verschiedene    verbessemngbeduerftige    Artikel  des 

Deutschen  Arzneibuches  V. 
Apoth.-Ztg.,  29,  p.  901. 

It  ih  stated  that  a  large  portion  of  the  extract  of  male  fern  made  in  Ger- 
many shows  a  crude  filicin  content  of  less  than  15  per  cent.,  while  the  Swls^ 
Pharmacopoeia  requires  a  content  of  26  to  28  per  cent.  The  author, 
therefore,  thinks  it  desirable  that  a  method  for  the  estimation  of  the  crude 
filicin  in  this  preparation  be  given  in  the  German  PharmacopcBia. 


6IBLJOGRAPSY  281 

E'we,  G.  E.  1^14 

Report  of  Committee  on  Drug  Market. 
Proc.  Penna.  Pharm.  Assoc,  37,  p.  125. 

The  author  reports  as  follows  on  the  oleoresins  examined: 

Four  samples  of  oleoresin  of  capsicum  were  found  to  be  pungent  m 
dilutions  of  1  to  150,000,  the  arbitrary  standard  of  H.  K.  MulforcT 
Company. 

Seven  samples  of  oleoresin  of  ginger  were  pungent  to  the  taste  in 
dilutions  of  1  to  20,000,  the  arbitrary  standard  of  H.  K.  Mulford  Company. 

Oiie  lot  of  oleoresin  of  cubeb  contained  the  waxy  deposit  which  the  U. 
S.  P.  directs  should  be  rejected. 

One  lot  of  oleoresin  of  say  palmetto,  ''U.  S.  P."  contained  15  per  cent, 
of  water  which  separated  on  standing.  It  also  contained  a  large  amount 
of  insoluble  matter   (p.  152.) 

Linke,  H.  1914 

Ergebnisse,    Beobachtungen    und    Betrachtungen    bei  der 

Untersuchung  unserer  Arzneimittel. 
Apoth.-Ztg.,  30,  pp.  606  and  628. 
The  results  obtained  in  the  examination  of  extract  of  male  fern,  in  bulk 

and  in  capsules,  obtained  from  various  sources  are  tabulated.      Especially 

the  extract  marketed  in  capsules  was  found  to  be  low  in  filicin  content. 

Patch,  E.  L.  1914 

Report  of  Committee  on  Quality  of  Medicinal  Products. 
Journ.  A.  Ph.  A.,  3,  p.  1283. 
A  sample  of  oleoresin  of  capsicum  examined  is  reported  as  having  been? 
found  to  be  insoluble  in  ether,  only  slightly  soluble  in  alcohol  and  almost 
completely  soluble  in  water  (p.  1298.) 

Rippetoe,  J.  R.  1914 

The  examination  of  some  drugs  with  special  reference  to* 

the  anhydrous  alcohol  and  ether  extracts,  and  ash. 
Am.  Journ.  Pharm.,  86,  p.  435. 

Four  samples  of  capsicum  are  reported  as  having  yielded  17.02  to  24.46" 
per  cent,  of  extract  to  alcohol,  and  16.49  to  17.88  per  cent  to  ether,  (p.  437.) 

Six  samples  of  cubebs  gave  8.87  to  11.04  per  cent,  of  alcoholic  extract^ 
and  7.68  to  9.80  per  cent,  of  ethereal  extract,    (p.  438.) 

Two  samples  of  Jamaica  ginger  yielded  4.98  to  5.5  per  cent,  of  extractive 
matter  to  alcohol,  and  2.79  to  4.97  per  cent,  to  ether.  Two  samples  of 
African  ginger  yielded  6.20  to  6.23  per  cent,  to  alcohol,  and  5.3  to  5.45- 
per  cent,  to  ether,    (p.  439.) 

Three  samples  of  lupulin  yielded  32.49,  55.18  and  57.06  per  cent.,, 
respectively,   of   ethereal  extract,    (p.   440.) 


282  ^U  MEZ— THE  GALENICAL.  OL.EORESINS 

Scoville,  W.  L.  1914 

Report  of  Committee  on  Quality  of  Medicinal  Products. 
Joura.  A.  Ph.  A.,  3,  p.  1283. 

It  is  stated  that  the  samples  of  cubebs  examined  during  the  year  gave 
from  18.1  to  22  per  cent,  of  oleoresin,  (p.  1287.) 

Vanderkleed,  C.  E.  1914 

Report  of  Committees  on  Drug  Market. 

Proc.  Penna.  Pharm.  Assoc,  37,  p.  125. 
On  page  160,  analytical  data  obtained  from   the  laboratory  of   H.   K. 
Mulford  Company    are    reported    showing    the  following  yield  of  oleoresin 
for   capsicum,  cubebs    and  ginger: 


Capsicum    (15  samples) 
Cubebs  (6   samples) 
African  ginger  (3  samples) 
Jamaica  ginger    (3  samples) 
Male  fern  (4  samples) 


Lowest 

Highest 

Yield, 

Yield 

Average. 

Per  cent. 

Per  cent. 

Per  cent 

13.0 

18.0 

16.0 

13.9 

19.8 

16.9 

8.50 

9.61 

9.0 

4.33 

5.75 

5.06 

6.85 

10.12 

8.23 

1915 


Male  fern  extract. 

Southall  Bros.  &  Barclay,  Ann.  Rep.,  22  and  23,  p.  17. 

The  filicin  content  of  five  samples  of  extract  of  male  fern  examined  is 
reported  as  having  varied  from,  20.4  to  27.7  per  cent.,  the  specific  gravity 
from  0.9885  to  1.030. 

Olickman,  L.  H.  1915 

Report  of  Committee  on  Drug  Market. 
Proc.  Penna.  Pharm.  Assoc,  38,  p.  138. 

Ten  lots  of  lupulin  examined  are  reported  to  have  yielded  the  following 
percentages  of  ether-soluble  matter:  55.5,  55.0,  57.1,  58.6,  54.7,  55.3,  44.2, 
€9.2,  and  68.2,  (p.  149.) 

Yanderkleed,  C.  E.  1915 

Report  of  Committee  on  Drug  Market. 
Proc.  Penna.  Pharm.  Assoc,  38,  p.  138. 
On  page  155,  the  following  data  concerning  the  yield  of  oleoresin  are 


BIBLIOGRAPHY  283 

reported  as  having  been  obtained  from  the  analytical  laboratory  of  H.  K. 
Mulford   Company. 

Lowest     Highest 

Yield.      Yield.  Average. 

Per  cent.  Per  cent.  Per  cent. 

Capsicum   (6  samples)                                      13.85         20.84  16.65 

African  ginger  (2  samples)                                7.99           8.90  8.44 

Jamaica  ginger   (1  sample)                               3.93           3.93  3.93 

Beringer,  G.  M.  1916 

The  reasons  for  some  of  the  changes  in  the  formulas  of  galeni- 
cals made  in  the  ninth  revision  of  the  United  States  Pharma- 
copoeia. 

Journ.  A.  Ph.  A.,  vol.  5,  No.  12,  p.  1390. 

It  is  stated  that  acetone  was  the  menstruum  directed  to  be  used  in  the 
preparation  of  the  oleoresins  by  U.  S.  P.,  eighth  revision,  on  account  of 
cheapness.  It  is  further  stated  that,  since  permission  has  been  obtained 
to  use  denatured  alcohol  in  the  manufacture  of  ether,  the  cost  of  the  latter 
has  been  reduced  to  such  an  extent  that  it  has  again  become  advantageous 
to  use  it  in  place  of  acetone.      Hence,  its  use  in  the  new  Pharmacopoeia. 


284 


DU  MEZ— THE  GALENICAL  OLEORESINS 


INDEX  TO  BIBLIOGEAPHY 


Oleoresin  of  Aspidium 

1891. 

Kuersten,  R. 

1824. 

Geiger,   Ph.   L. 

1891. 

Poulsson,  E. 

1824. 

Morin 

1891. 

Raymon 

1826. 

Buchner,    A. 

1891. 

Eeuter,  Ludwig 

1826. 

Von  Esenbeck,  Nees 

1892. 

Beringer,  G.  M. 

1826. 

Peschier,  Ch. 

1892. 

Duhourcau 

1827. 

Batso,  V. 

1892. 

Kobert 

1827. 

Brandes,  E. 

1892. 

Sherrard,  C.  0. 

1827. 

Buchner,  A. 

1892. 

Weppen  &  Lueders 

1827. 

Van  Dyk 

1892. 

Dieterich 

1827. 

Geiger,  Ph.  L. 

1893. 

Bechurts  &  Peters 

1827. 

Tilloy 

1893. 

Dieterich 

1827. 

Zeller 

1893. 

Gehe  &  Co. 

1828. 

Meylink 

1894. 

Poulsson,  E. 

1828. 

Peschier,  Ch. 

1894. 

Dieterich 

1828. 

Winkler,  F.  L. 

1894. 

Hell  &  Co. 

1829. 

Allard 

1895. 

Van  Aubel 

1829. 

Haendess 

1895. 

Boehm,  R. 

1829. 

Voget 

1895. 

Dieterich 

1844. 

Hornung  ' 

1896. 

Bocchi,  I. 

1845. 

Luck 

1896. 

Daccomo  and  Scoccianti 

1851. 

Bock 

1896. 

Dieterich 

1851. 

Luck,  E. 

1896. 

Kraft,  F. 

1852. 

von  der  Marck 

1896. 

Caesar  and  Loretz 

1859. 

Procter,  Wm.,  Jr. 

1897. 

Boehm,   R. 

1861. 

Pavesi 

1897. 

Candussio 

1871. 

Hager 

1897. 

Lauren,   W. 

1875. 

Patterson,   J. 

1897. 

Madsen,   H.  P. 

1876. 

Kruse 

1897. 

Caesar  and  Loretz 

1878. 

Cressler,    C.    H. 

1897. 

Dieterich 

1878. 

Rohn,  E. 

1897. 

Gehe  &  Co. 

1879. 

Kennedy 

1897. 

Chem.   C^tralb. 

1881. 

Bowman,  J. 

1898. 

Bellingrodt,  Fr. 

1881. 

Seifert,  0. 

1898. 

Dieterich,  Karl 

1883. 

Maish,  J.  M. 

1898. 

Duesterbehn,  F. 

1884. 

Kramer 

1898. 

Katz,  Julius 

1886. 

Berenger-Feraud 

1898. 

Lefils 

1887. 

Kremel,  A. 

1898. 

Miehle,  Feodor 

1888. 

Keefer,  C.  D. 

1898. 

Plzak,  F. 

1888. 

Trimble,  H. 

1898. 

Caesar  &  Loretz 

1889. 

Greenwalt,  W.  G. 

1898. 

Gehe  &  Co. 

1891. 

Dieterich 

1898. 

Pharm.  Centralh. 

BIBLIOQRAPHY 


285 


Oleoresin  of  Aspidium. — Con. 


Oleoresin  of  Aspidium. — Con. 


1899. 

Hausmann,  A. 

1912. 

Caesar  &  Loretz 

1899. 

Am.  Drugg.  &  Pharm.  Eec. 

1912. 

Evans  Sons  Lescher  &  Webb 

1899. 

Caesar  &  Loretz 

1912. 

Merck's  Eep. 

1900. 

Caesar  and  Loretz 

1912. 

Southall  Bros.  &  Barclay 

1900. 

Geh€  &  Co. 

1913. 

Bohrisch,  P. 

1901. 

Linda,   O. 

1913. 

Du  Mez,  A.  G. 

1901. 

Matzdorff,  M. 

1913. 

Goris  &  Voisin 

1901. 

Schmidt,  M.  E. 

1913. 

Harrison  and  Self 

1901. 

Stoeder 

1913. 

Hill,  C.  A. 

1901. 

Caesar  and  Loretz 

1913. 

Parry,  E.  J. 

1901. 

Dieterich 

1913. 

Yagi,  E. 

1902. 

Buttin,  L. 

1913. 

Caesar  and  Loretz 

1902. 

Kraft,  F. 

1913. 

Evans  Sons  Lescher  &  Webb 

1902. 

Caesar  and  Loretz 

1913. 

Southall  Bros.  &  Barclay 

1903. 

Pendorff,  0. 

1914. 

Bohrisch,  P. 

1903. 

Schmidt,  E. 

1914. 

Linke,  H. 

1903. 

Caesar  and  Loretz 

1914. 

Vanderkleed,  C.  E. 

1903. 

Dieterich 

1914. 

Caesar  &  Loretz 

1903. 

Southall  Bros.  &  Barclay 

1914. 

Journ.  A.  Ph.  A. 

1904. 

Caesar  and  Loretz 

1914. 

Riedel's  Ber. 

1904. 

Dieterich 

1915. 

Sherman,  H.  B. 

1905. 

Kiezka,  M. 

1915. 

Southall  Bros.  &  Barclay. 

1905. 

Pharm.  Ztg. 

1905. 

Caesar  and  Loretz 

Oleoresin  of  Capsicum 

1905. 

Dieterich 

1849. 

Procter,  Wm.  Jr. 

1906. 

Naylor,  A.  H 

1853. 

Bakes,  W.  C. 

1906. 

Eoeder,   Ph. 

1864. 

Parrish,  E. 

1906. 

Wollenweber,  W. 

1872. 

Maish,  J.  M. 

1906. 

Apoth.-Ztg. 

1873. 

Bucheim 

1906. 

Caesar  &  Loretz 

1888. 

Trimble,  H. 

1908. 

Caesar  and  Loretz 

1892. 

Sherrad,  C.  C. 

1908. 

Vanderkleed,  C.  E. 

1898. 

Winton,  Ogden  and  MitchelL 

1909. 

Dunn,  J.  A. 

1903. 

Beythien 

1909. 

Vanderkleed,  C.  E. 

1903. 

Southall  Bros.  &  Barclay 

1909. 

Caesar  &  Loretz 

1905. 

Vanderkleed,  C.  E. 

1910. 

Dohme  &  Engelhardt 

1905. 

Am.  Drugg.  &  Pharm.  Rec. 

1910. 

Gandini,  V. 

1907. 

Patch,  E.  L. 

1910. 

Gane  &  Webster 

1908. 

Patch,  E.  L. 

1910. 

Caesar  &  Loretz 

1908. 

Vanderkleed,    C.    E. 

1911. 

Parry,  E.  J. 

1909. 

Vanderkleed,  C.  E. 

1911. 

Pearson,  W.  A. 

1910. 

Brown,    L.   A. 

1911. 

Rosendahl,  H.  V. 

1910. 

Eldred,  F.  R. 

1911. 

Chem,  &  Drng. 

1910. 

Southall  Bros.  &  Barclay 

1911. 

Brit.  &  Col.  Drugg. 

1910. 

Vanderkleed,  C.  E. 

1911. 

Caesar  &  Loretz 

1911. 

Deane,  Harold 

1911. 

Evans  Sons  Lescher  &  Webb 

1911. 

Vanderkleed,  C.  E. 

1912. 

Roberts,  H.  G. 

1912. 

Vanderkleed,  C.  E. 

286 


DU  MEZ— THE  GALENICAL  OLEORESINS 


Oleoresin  of  Capsicum. — Con. 

1913.  Chem.  &  Drugg. 

1913.  Engelhardt,  H. 

1913.  Patch,  E.  L. 

1912.  Evans  Sons  Lescher  &  Webb 

1912.  Johnson  &  Johnson 

1913.  Unmey,  J.  C. 

1913.  Vanderkleed,  C.  E. 

1914.  Patch,  E.  L. 
1914.  Rippetoe,  J.  R. 
1914.  Vanderkleed,  C.  E. 
1914.  Journ.  A.  Ph.  A. 

1914.  Riedel's  Ber. 

1915.  Vanderkleed,  C.  E. 

Oleoresin  of  Cube!) 

1828.  Dublane,  H. 

1828.  Oberdoerffer 

1838.  Hausmann 

1846.  Bell 

1846.  Procter,  Wm.,  Jr. 

1857.  Garot  and  Schaeuffele 

1857.  Landerer,  X. 

1859.  Procter,  Wm.,  Jr. 

1863.  Girtle 

1865.  Bernatzik,  W. 

1866.  Procter,  Wm.,  Jr. 

1866.  Rittenhouse,  H.  N. 

1867.  Paul,  C. 

1867.  Pile 

1868.  Heydenreich,  F.  V. 
1872.  Maish,  J.  M. 
1877.  Griffin,  L.  P. 
1877.  WolflF,  L. 

1883.  Maish,  J.  M. 

1887.  Kremel,  A.  ' 

1887.  Gehe  &  Co. 

1888.  Trimble,  H. 

1892.  Sherrard,  C.  C. 

1893.  Dieterich 

1894.  Bedall 

1894.  Hell  &  Co. 

1895.  Hyers,  P. 

1895.  Dieterich  ^ 

1895.  Gehe  &  Co. 

1905.  Vieth,  R.  

1905.  Dieterich  -??       t  •  - 


Oleoresin  of  Cubeb. — Con. 

1907.  Blome,  W.  H. 

1907.  Smith,  A.  W. 

1907.  Evans  Sons  Lescher  &  Webb 

1908.  Vanderkleed,  C.  E. 

1909.  Vanderkleed,  C.  E. 

1909.  Chem.   &  Drugg. 

1910.  Gane,  E.  H. 
1910.  Vanderkleed,  C.  E. 

1910.  Southall  Bros.  &  Barclay 

1911.  Southall  Bros.  &  Barclay 

1911.  Vanderkleed,  C.  E. 

1912.  Dohme  &  Engelhardt ' 
1912.  Gluecksmann,  G. 

1912.  Vanderkleed,  C.  B. 

1913.  Dohme  &  Engelhardt 

1913.  Vanderkleed,  C.  E. 

1914.  Maines  and  Gardner 
1914.  Rippetoe,   J.  R. 
1914.  Scoville,  W.  L. 
1914.  Vanderkleed,  C.  E. 
1914.  Journ.  A.  Ph.  A. 
1914.  Riedel'B  Ber. 

Oleoresin  of  Ginger 

1834.  Beral 

1849.  Procter,  Wm.,  Jr. 

1859.  Procter,  Wm.,  Jr. 

1866.  Rittenhouse,  H.  N. 

1867.  Pile 

1872.  Maish,  J.  M. 

1877.  Wolflf,  L. 

1879.  Thresh 

1886.  Jones,   E.   W.  : 

1888.  Trimble,  H. 

1891.  Riegel,  S.  J. 

1892.  Sherrard,  C.  C. 

1893.  Dyer  and  Gilbard 

1895.  Davis,  R.  G. 

1896.  Liverseege 

1897.  Glass  and  Thresh 
1901.  Bennet 

1903.  Ballard 

1903.  Southall  Bros.  &  Barclay 

1905.  Helfenberger  Ann. 

1908.  Spaeth,  Eduard 

1908.  Vanderkleed,  C.  E. 

1909.  Patch,  E.  L. 


BIBLJOGRAPHT 


287 


Oleoresin  of  Ginger. — Con. 

1909.  Vanderkleed,    C.    E. 

1910.  La  Wall,  C.  H. 

1910.  Vanderkleed,  C.  E. 

1911.  Beythien,  Hemple  &  Others 

1911.  Vanderkleed,  C.  E. 

1912.  Hooper,  D. 
1912.  Patch,   E.   L. 

1912.  Vanderkleed,  C.  E. 

1913.  Engelhardt,  H.  • 
1913.  Patch.  E.  L. 
1913.  Vanderkleed,  C.  E. 

1913.  Chem.  &  Drugg. 

1914.  Eippetoe,  J.  K. 
1914.  Vanderkleed,  C.  E. 

1914.  Journ.  A.  Ph.   A. 

1915.  Vanderkleed,    C.    E. 


Oleoresin 
1825. 
1829. 
1859. 
1877. 
1888. 
1892. 
1903. 
1913. 
1913. 
1913. 
1914. 


of  Pepper 
Meli 

Carpenter,  G.   W. 
Procter,  Wm.  Jr. 
Wolff,  L. 
Trimble,  H. 
Sherrard,  C.  C. 
Ballard 

La  Wall,  C.  H. 
Engelhardt,   H. 
Patch,  E.  L. 
Journ.  A.    Ph.  A. 


Oleoresin  of  Lupulin 

1823. 

Planche 

1853. 

Livermore 

1859. 

Procter,  Wm.  Jr. 

1869. 

Kump,  C. 

1888. 

Trimble,   H. 

1892. 

Sherrard,  C.  C. 

1907. 

Van  der  Harst,  J.  C. 

1908. 

Dohme  &  Engelhardt 

1909. 

Bernegau,  L.  H. 

1909. 

Dohme  &  Engelhardt 

1909. 

Parson,  W.  A. 

1911. 

Bernegau,  L.  H. 

1911. 

Francis,  J.  H. 

1913. 

Gane,  E.  H. 

1913. 

Engelhardt,   H. 

1913. 

Osborne,  0.  T, 

1913. 

Patch,  E.  L. 

1914. 

Eippetoe,  J.  E. 

1915. 

Glickman,  L.  H. 

Oleoresin  of  Parsley  Fruit 

1877. 

Wolff,  L. 

1892. 

Beringer,   G.  M. 

1906. 

Merck's  Ann.  Eep. 

1909. 

Evans  Sons,  Lescher  &  Webb 

1913. 

Engelhardt,  H. 

1913.  Osborne,  O.  P. 

1914.  Jonm.  A.  Ph.  A. 


Oleoresin  of  AlTcanet  Boot 
1892.     Gehe  &   Co. 

Oleoresin   of  Annatto  ! 

1895.     Gehe  &  Co. 

Oleoresin  of  Cardamom  Seed 
1849.     Procter,  Wm.,  Jr. 
1859.  "  '«       <' 

Oleoresin  of  Chenopodvum 
1849.     Procter,  Wm.,  Jr. 
1877.    Wolff,  L. 

Oleoresin  of  Clove 

1849.    Procter,  Wm.,  Jr. 

Oleoresin  of  Coni/um  Leaves 
1870.    Lefort,  M.  J. 

Oleoresin  of  Pepo 
1890.     Minner,  L.  A. 

Oleoresin  of  Pyrethrum 
1849.    Procter,  Wm.,  Jr. 
1859.  **         *'       " 

1902.    Southall  Bros,  and  Bardaj 
1911.         **  *'        "         ** 


Oleoresin  of  Santonica 
1830.    Schuppmann 
1849.    Procter,  Wm.,  Jr. 
1877.    Wolff,  L. 


•288 


DU  MEZ— THE  GALENICAL.  OLEORESINS 


Oleoresin  of  Savine 

'    1849.    Procter,  Wm.,  Jr. 

Oleoresin  of  Saw  Palmetto 
1914.     E'we,  G.  E. 

Oleoresin  of  Xanthoxylum 
1849.     Procter,   Wm.,  Jr. 


Oleoresins    (General) 

1869.  Squibb,  E. 

1873.  Remington,  J.  P. 

1887.  Lippincott,    C.   P. 

1900.  Maish,  H.  C. 

1905.  Francis,  J.  M. 

1905.  Drug  Topics 

1916.  Beringer,  G.  M. 


C-UIDS 

Information  of  the  encyclopaedic  dictionary  type  is  being  edited  and 
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2. 
3. 
4. 

5. 

6. 

8. 

9. 
10. 
11. 
12. 
13. 
14. 
15. 
1(]. 
17. 
IS. 
19. 
20. 
21. 
22. 
23. 
24. 
25. 
26. 


Anaesthesin 

Drug 

vT.  O.  Schlotterbeck   (Biography) 

J.  O.  Schlotterbeck   (Original  Publications) 

J.  O.  Schlotterbeck  (Miscellaneous    Writings, 

views) 
Liquor*  Potassii  Arsenitis,  U.  S.  P.  1890 
Linogen 
Linoliment 
Linoval 
Parogen  (um) 
Penetrole 
Petrogen 

Petrolatum  Saponatum 
Petroliment 
Petroxolin  (um) 
Valselol 
Valsol 
Vasapon 
Vascosan 
Vaselon 
Vaseloxyne 
Vasenol 
Vasogen(um) 
Vasol 

Vasoliment  (um) 
Vasopolent  (^um ) 
Vasoval 


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